Cell Tissue Res DOI 10.1007/s00441-015-2212-x
REVIEW
The roles of endoplasmic reticulum stress response in female mammalian reproduction Yanzhou Yang 1 & Xiuying Pei 1 & Yaping Jin 3 & Yanrong Wang 1 & Cheng Zhang 2
Received: 1 March 2015 / Accepted: 1 May 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Endoplasmic reticulum stress (ERS) activates a protective pathway, called the unfold protein response, for maintaining cellular homeostasis, but cellular apoptosis is triggered by excessive or persistent ERS. Several recent studies imply that the ERS response might have broader physiological roles in the various reproductive processes of female mammals, including embryo implantation, decidualization, preimplantation embryonic development, follicle atresia, and the development of the placenta. This review summarizes the existing data concerning the molecular and biological roles of the ERS response. The study of the functions of the ERS response in mammalian reproduction might provide novel insights into and an understanding of reproductive cell survival
This work was supported by the Natural Science Foundation of China (no. 81260110); the open project of Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Ningxia Medical University; Beijing Municipal Natural Science Foundation (no. 5142003); and the National Natural Science Foundation of China (no. 31300958). * Yanzhou Yang [email protected] * Cheng Zhang [email protected] 1
Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, Ningxia Medical University, Yinchuan, Ningxia 75004, People’s Republic of China
2
College of Life Science, Capital Normal University, Beijing 100048, Peoples’ Republic of China
3
Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
and apoptosis under physiological and pathological conditions. The ERS response is a novel signaling pathway for reproductive cell survival and apoptosis. Infertility might be a result of disturbing the ERS response during the process of female reproduction. Keywords Endoplasmic reticulum stress response . Follicle atresia . Embryo implantation . Decidualization . Embryonic development . Placental development
Abbreviations ERS Endoplasmic reticulum stress UPR Unfolded protein response Grp78/Bip Glucose-regulated protein 78-kDa/immunoglobulin heavy chain binding protein in pre-B cells ATF6α Activating transcription factor 6α IRE1α Inositol requiring enzyme 1α PERK Pancreatic ER kinase CHOP C/EBP-homologous protein growth arrest and DNA damage-inducible gene 153 GADD153; DNA-damage inducible transcription 3 DDIT3 JNK c-Jun N-terminal kinase eIF2α Eukaryotic initiation factor 2α Xbp1(U) Unspliced X-box binding protein Xbp1(S) Spliced X-box binding protein
Introduction The endoplasmic reticulum (ER) is an important organelle for protein folding, transport, and synthesis. However, the microenvironment of the ER can be disturbed by the depletion of Ca2+, hypoxia, and the dysfunction of N-terminal glycosylation, causing ER stress (ERS; Kaufman 1999; Koumenis
Cell Tissue Res
2006). As a consequence of ERS, unfolded and misfolded proteins accumulate in the ER. When this occurs, the ERS response (unfold protein response, UPR) is initiated to relieve ERS and to promote cell survival (Kaufman 2002; Xu et al. 2005; Yang et al. 2014). Three signaling transduction pathways are involved in the UPR: (1) PERK (pancreatic ER kinase)/eIF2α (eukaryotic initiation factor 2α)/ATF4 (activating transcription factor 4), (2) IRElα (inositol requiring enzyme 1α)/XBP-1 (X-box-binding protein), and (3) ATF6α (activating transcription factor 6α; Fung and Liu 2014; Jheng et al. 2014; Mei et al. 2013). Through the UPR, the ER load is relieved by three processes, as follows: (1) a reduction of the entry of newly synthesized proteins into the ER through attenuating protein translation; (2) an increase in the proteinfolding capacity through upregulating ER gene expression; and (3) a degradation of misfolded and unfolded proteins through ER-associated degradation (ERAD) and lysosomemediated autophagy (Fig. 1; Ellgaard and Helenius 2003; Lemus and Goder 2014; Yorimitsu and Klionsky 2007). The misfolded and unfolded proteins are mainly degraded by ERAD through the ubiquitin-proteasome system (termed as ERAD I; Fujita et al. 2007; Nakatsukasa et al. 2014), but lysosome-mediated autophagy is triggered when the ERAD is impaired, and therefore, lysosome-mediated autophagy has been referred to as an ERAD II pathway (Fujita et al. 2007; Hetz et al. 2009). However, when the UPR fails to deal with the unfolded and misfolded proteins, cellular apoptosis is triggered by excessive or persistent ERS (Malhotra and Kaufman 2007; Oh et al. 2012; Samali et al. 2010; Sheveleva et al. 2012; Tersey et al. 2012; Xu et al. 2005) through the activation of the CHOP (C/EBP-homologous protein; growth arrest and DNA damage-inducible gene 153, GADD153; DNA—damage inducible transcription 3, DDIT3), c-Jun N-terminal kinase (JNK), and caspase-dependent pathways, with caspase-4 in human and caspase-12 in rodents (Fig. 1; Hitomi et al. 2004; Li et al. 2011; Siman et al. 2001; Szegezdi et al. 2006; Urano et al. 2000). Glucose-regulated protein 78-kDa (GRP78, also known as Bip) is an ER chaperone that interacts with PERK, IRElα, and ATF6α in the ER membrane, but Grp78 dislocates from PERK, IRElα, and ATF6α and enters the ER lumen in the presence of the ERS response. The function of Grp78 is antiapoptotic during the ERS response (Zheng et al. 2014); CHOP (Zhang et al. 2014; Zheng et al. 2014; Zinszner et al. 1998), JNK (Simon-Szabó et al. 2014; Wang et al. 2014), and caspase-4/12 (Hong et al. 2014; Zhang et al. 2014) are proapoptosis and activate ERS-mediated apoptosis. CHOP is downstream of three UPR signaling pathways, and one or more is UPR-signaling-dependent. JNK is IRElα-signalingdependent. Caspase-4/12 is independent of the three UPR signaling pathways. JNK is phosphorylated and caspase-4/12 is cleaved when apoptosis is triggered by ERS (Fig. 1; Fung and Liu 2014; Jheng et al. 2014; Mei et al. 2013).
Previous studies have reported that the ERS response occurs in several physiological and pathological process, including the immune response (Hasnain et al. 2012; Todd et al. 2008), inflammation (Hasnain et al. 2012), autophagy (Bernales et al. 2006; Ogata et al. 2006; Shimada et al. 2011), and metabolic diseases such as diabetes (Hasnain et al. 2012; Lipson et al. 2006), bone and joint diseases (Hasnain et al. 2012), neurogenic diseases such as Alzheimer’s disease (Salminen et al. 2009), cancer (Moenner et al. 2007), and viral replication (Li et al. 2013). In addition, some recent research has suggested that the ERS response is also involved in female reproduction. This review examines the functions of ERS in mammalian female reproduction. The study of the ERS response function in reproduction should broaden our understanding of the way that reproductive cells and tissues maintain their microenvironment and might reveal novel signaling pathways that regulate apoptosis in reproductive tissues under physiological and pathological conditions.
Involvement of ERS response in follicle atresia Follicular atresia occurs via apoptosis of the ovarian granulosa cells (Hughes and Gorospe 1991; Rajakoski 1960) in mice (Hughes and Gorospe 1991), cows (Jolly et al. 1994), ewes (Murdoch 1995), and pigs (Liu et al. 2003; Sugimoto et al. 1998), and infertility is caused by excessive follicle atresia. Apoptotic signaling pathways mediated by death-receptorand mitochondria-mediated type I programmed cell death (also called apoptotic cell death) systems are active in granulosa cells in mammalian ovaries (Jiang et al. 2003; Manabe et al. 2004; Matsuda-Minehata et al. 2006). In addition, previous studies have suggested that follicle atresia is induced by autophagy, which is type II programmed cell death (also called autophagic cell death; Choi et al. 2010, 2013). Therefore, follicle atresia is regulated by apoptotic and autophagic cell death, but whether apoptotic and autophagic cell death interact with each other during follicle atresia remains unknown. Cellular apoptosis is initiated by excessive or persistent ERS. GRP78 is an ER chaperone with multiple functional roles in protein processing and cellular protection (Kogure et al. 2013). The expression of Grp78 in ovarian granulosa cells implies that ovarian granulosa cell apoptosis is induced by ERS and that ERS is a signaling pathway in goat ovarian granulosa cell apoptosis and follicle atresia (Lin et al. 2012). Compared with normal goat follicles, Grp78 and CHOP are remarkably upregulated in apoptotic granulosa cells of the early atretic follicle, and Grp78 is downregulated, whereas CHOP is further upregulated, during the process of atresia. These data are further supported by cell culture experiments in vitro. ERS is induced by the ERS inducer tunicamycin. In accordance with Lin’s results, Yang’s research has further suggested that the apoptosis in mouse ovarian granulosa cells is
Cell Tissue Res
Fig. 1 Endoplasmic reticulum (ER) stress (ERS) and unfold protein response (UPR) signaling pathway. Bip (also called glucose-regulated protein 78-kDa) combines with activating transcription factor 6 (ATF6), inositol requiring enzyme 1α (IRE1α), and pancreatic ER kinase (PERK) in the ER membrane. Bip translocates from the membrane to the lumen in response to ERS. ATF6 translocates from the ER into Golgi body and is processed by Site-1 (S1P) and Site-2 protease (S2P). IRE1α and PERK are activated by phosphorylation (p). The three UPR signaling pathways
(yellow arrows), namely C/EBP-homologous protein; growth arrest and DNA damage-inducible gene 153, GADD153; DNA—damage inducible transcription 3, DDIT3 (CHOP), caspase-12, and c-Jun N-terminal kinase (JNK), are activated to relieve the ER load by (black boxes) increasing the protein-folding capacity, attenuating protein translation, and degrading unfolded and misfolded protein (Xbp1(U) unspliced X-box binding protein, Xbp1(S) spliced X-box binding protein, eIF2α eukaryotic initiation factor 2α, ERAD ER-associated degradation)
triggered by ERS (Yang et al. 2013a, b). In addition, ovarian granulosa cell apoptosis is triggered by ERS, under conditions of obesity and polycystic ovary syndrome (PCOS), and ERSmediated apoptosis might be a potential pathogenic mechanism of obesity and PCOS (Wu et al. 2010; Zhang et al. 2007). Mouse cumulus-oocyte complexes have been cultured in vitro and exposed to lipid-rich follicular fluid, causing the induction of ERS and the impairment of oocyte maturation, unlike complexes exposed to lipid-poor follicular fluid and complexes matured in vivo (Yang et al. 2012). Therefore, ERS is a novel mechanism involved in ovarian granulosa cell apoptosis and follicle atresia caused by physiological and pathological conditions. The way that ERS affects the three UPR signaling pathways in granulosa cell apoptosis is not fully understood. Whether the function of ERS in granulosa cell apoptosis is closely related to the death receptor, mitochondria-mediated apoptosis, and autophagymediated granulosa cell death is unknown; this potential mechanism needs to be explored further.
Involvement of ERS response in preimplantation embryonic development The ERS response is an evolutionarily conserved mechanism and is indispensable for preimplantation embryonic development. Grp78 is minimally detected in mouse zygotes, weakly detected from the two-cell to the morula stage, but strongly detected in the blastocyst, indicating that Grp78 regulates the development of the blastocyst (Kim et al. 1990). Further, Grp78−/− (homozygous knockout) embryos are unable to survive beyond the peri-implantation stage and exhibit periimplantation lethality. These embryos do not grow in culture and exhibit increased apoptosis in the inner cell mass and reduced proliferation (Luo et al. 2006). Therefore, Grp78 is essential for embryonic growth and protects the inner cell mass from apoptosis. In addition, CHOP is only detected before the eight-cell stage in vivo but has been found in the zygote to blastocyst stages when the embryo is cultured in KSOM media in vitro
Cell Tissue Res
(Fleming et al. 1997). In cow embryos cultured in vitro in the presence of a DNA-damaging reagent, CHOP expression increases remarkably in response to ERS (Fontanier-Razzaq et al. 2001). Additionally, the existence of other ERS response-related proteins, such as Luman recruiting factor (Yang et al. 2013a, b) and SMILE/Zhangfei (Lin et al. 2013), in the zygote to blastocyst stages is further evidence that preimplantation embryonic development is regulated by ERS response. Preimplantation embryonic apoptosis and developmental arrest frequently occur during embryo culture in vitro and embryonic cryopreservation, and the survival rates are low. However, the mechanism of embryonic apoptosis and developmental arrest remain unknown. The mechanism by which the embryo adapts to the culture microenvironment in vitro is also unknown. The hypothesis that the ERS response regulates early embryonic development stems from several findings. When preimplantation pig embryos are cultured in vitro in the presence of the ERS inducer tunicamycin, the apoptotic rate is significantly higher than that of the control, and the capacity to develop into a blastocyst is significantly lower than that of the control. In addition, the XBP-1 mRNA level is remarkably upregulated in the experimental group compared with the control. In contrast, when the ERS inhibitor TUDCA (tauroursodeoxycholic acid) is added, the capacity to develop into a blastocyst is significantly higher than that of the control. Therefore, TUDCA protects preimplantation embryos from apoptosis induced by ERS (Kim et al. 2012). Indeed, inhibition of ERS improves mouse embryonic development and decreases ERS-induced apoptosis (Zhang et al. 2012). Furthermore, the consistent results suggest that the UPR prevents blastocyst formation during preimplantation embryo development in vitro, and that TUDCA reverses this outcome (Basar et al. 2014). Embryonic cryopreservation is a common assistedreproduction technique, but the effect of vitrification on preimplantation embryonic development is not clear. Whether ERS and the UPR are initiated during standard embryonic treatments, including embryo collection, culture, and vitrification, is unknown. Abraham’s studies have suggested that the main ERS response pathway is initiated at all stages of the preimplantation embryo, especially at the eight-cell, morula, and blastocyst stages (Abraham et al. 2012). Moreover, the IRE1α signaling pathway is activated in freshly collected embryos but is not initiated by embryonic vitrification (Abraham et al. 2012). DDK syndrome is a polar early embryonic lethal phenotype that occurs when DDK females are mated with males of other inbred mouse strains, and lethality occurs during the transformation from morula to blastocyst (Tomita 1960; Wakasugi 1973, 1974). Analysis of the gene expression in morulae of DDK×DDK (high survival
rate) and DDK×C57BL/6 (low survival rate) crosses have revealed that many UPR genes are upregulated, Grp78 accumulates in the ER, the structure of the ER is abnormal, and the expression of the ERS-response-related proteins HERPUD1 (homocysteine-inducible, ER stress-inducible, ubiquitin-like domain member 1) and ATF4 are upregulated in the DDK×C57BL/6 embryo. These results suggest that DDK syndrome, which causes early embryonic lethality, is controlled by an ERS response signaling pathway (Hao et al. 2009). In summary, the ERS response maintains preimplantation embryonic development and adaptation to the microenvironment in vivo and in vitro, but ERS-associated apoptosis is triggered by excessive ERS, making it a key component of early embryonic lethality, embryonic apoptosis, and developmental arrest.
Involvement of ERS response in embryo implantation and decidualization Embryo implantation is a critical step in female mammalian reproduction and occurs through an intricate interaction between the activated blastocyst and receptive uterus (Dey et al. 2004; Wang and Dey 2006). The embryo trophectoderm initiates attachment to the uterine epithelium and then invades the endometrium during implantation (Hayashi et al. 2009; Kimber and Spanswick 2000; Lee and DeMayo 2004). Estrogen (E2) and progesterone (P4) are indispensable for the implantation process (Hayashi et al. 2009; Huet-Hudson et al. 1989). Understanding of the complete mechanism of embryonic implantation is lacking. Many ERS response genes and proteins are upregulated during embryo implantation, indicating that the ERS response is essential for the embryo implantation. The transcript of Grp78 is significantly increased in the pregnant mouse uterus on day 5 when embryo implantation occurs, and the function of Grp78 is regulated by E2 (Simmons and Kennedy 2000). Consistent with the Grp78 mRNA level, Grp78 protein significantly increases in the pregnant mouse uterus on day 5, especially in the implantation site (Lin et al. 2014; Reid and Heald 1970), and these results suggest that increased Grp78 in the pregnant mouse uterus plays important roles in embryo implantation through the UPR and ERS. Additionally, the upregulation of the calcium-binding protein S100P in the human uterine epithelium during embryo implantation (Tong et al. 2010; Zhang et al. 2012), the embryo implantation failure caused by the downregulation of the calcium-binding protein S100A11 (Liu et al. 2012), and the abundant expression of calcium-transport genes in reproductive tissues in a
Cell Tissue Res
distinct manner (Choi et al. 2011) suggest that calcium regulates embryo implantation, and that calcium-channel blockers might provide new targets for female contraceptives (Banerjee et al. 2009, 2011). Nevertheless, ERS is triggered by a disturbance of Ca2+ homeostasis, and ERS and the UPR play an important role in the maintenance of Ca2+ homeostasis (Dai et al. 2012; Park et al. 2010). Therefore, our limited knowledge leads us to speculate that calcium regulates embryo implantation through ERS and the UPR. Indeed, the expression of ERS genes in the uterus is changed in calbindin-D(9 k) and -D(28 k) knockout mice (Jung et al. 2012). A previous study has suggested that the cellular apoptosis and the cellular homeostasis in the uterus are regulated by the ERS response. E2 and P4 regulate cellular apoptosis in the uterus. E2 induces apoptosis of the uterine epithelium, whereas P4 represses it (Terada et al. 1989). P4 is induced by the ERS response pathway (Jung et al. 2012). Following implantation, extensive proliferation and differentiation of stromal cells into decidual cells occurs to establish a vascular relationship with maternal tissue (Dey et al. 2004; Hayashi et al. 2009; Lim et al. 2002; Wang and Dey 2006). In abortive uterine decidual cells, ERS is caused by increased oxidative stress, suggesting that ERS and oxidative stress play important roles in early pregnancy loss (Gao et al. 2012; Liu et al. 2011). However, regardless of whether ERS is initiated under physiological conditions or not, previous studies have suggested that, compared with the control, the expression of Grp78 in mouse decidual uterus does not change significantly (Simmons and Kennedy 2000), suggesting that ERS might not be involved in decidualization. In contrast, our previous studies have suggested that Grp78 is remarkably upregulated in pregnant mouse uteri at day 5 (embryo implantation has occurred) and days 6–8 (decidualization; Lin et al. 2014). These results indicate that ERS might be involved in decidualization. Our research has revealed that the ERS-response-regulated protein Luman (Lan et al. 2013) and Luman recruiting factor (Yang et al. 2013a, b) are upregulated in pregnant mouse uteri during day 5 and days 6–8 and further suggests that ERS regulates embryonic implantation and decidualization. Another ERSresponse-associated protein, SMILE/Zhangfei, is also detectable in implantation sites but not in inter-implantation sites (Lin et al. 2013). These results further imply that the ERS response regulates embryo implantation and decidualization. In summary, physiological levels of ERS are involved in embryo implantation and decidualization, and implantation failure and early pregnancy loss are caused by abnormal ERS. These data provide novel insight into the mechanism of implantation failure and early pregnancy loss.
Involvement of ERS response in placenta function The placenta is indispensable for the embryo, and fetal growth restriction, fetal death, and birth defects are caused by placental malfunction (Watson and Cross 2005). Recent studies have suggested that increased ERS is closely related to placental development and fetal growth restriction (Iwawaki et al. 2009; Lian et al. 2011; Yung et al. 2008). Administration of CdCl2 to a pregnant mouse on day 9 (4.5 mg/kg) via intraperitoneal injection resulted in placental cell proliferation inhibition and apoptosis through the upregulation of Grp78 and other ERS-response-induced molecular chaperones. eIF2α of the PERK pathway was phosphorylated, and CHOP was upregulated (Wang et al. 2012). In the fetal growth-restricted placenta, ERS is significantly increased. Decreased placental cell proliferation and apoptosis and increased ERS might be the main reasons for the decreased placental growth (Burton et al. 2009; Yung et al. 2008). In addition, active PERK-peIF2α and ATF6α signal pathways have been detected, and XBP1(U) (unspliced Xbox-binding protein) and ATF6α protein remarkably increase in the fetal growth-restricted placenta (Lian et al. 2011). Compared with the decidual tissue of the normal pregnant placenta, many ERS response genes are significantly upregulated in placental decidual tissue in the case of preeclampsia (Løset et al. 2011). IRE1α is an important target gene in the ERS response pathway, and the widespread expression of IRE1α in the mouse is indispensable for female mammalian development (Tirasophon et al. 1998; Urano et al. 2000). IRE1α, Grp78, and EDEM (ER-degradation enhancing α-mannosidase-like protein) are strongly expressed in the mouse placenta, and XBP1(S) (spliced X-box-binding protein) mRNA and the active form of the PERK-peIF2a and ATF6α proteins are also detected in the placenta (Iwawaki et al. 2009). In addition, XBP1 has been shown to be essential for mouse placental development (Iwawaki et al. 2009). These results suggest that ERS is indispensable for the growth of the placenta. However, IRE1α knockout mice die on day 12.5 as a result of impaired function of vascular endothelial growth factor and the placental labyrinth layer. Furthermore, similar results have suggested that the placental morphology is impaired and low birth weight is caused by prolonged ERS through a decrease in the expression of vascular endothelial growth factor receptors 1 and 2 (Kawakami et al. 2014). These results suggest that physiological intercommunication occurs between placental angiogenesis and the ERS response (Iwawaki et al. 2009). In summary, these data suggest that ERS is mediated in placental development, but that the function of the placenta is impaired by both loss of ERS response and excessive ERS.
Cell Tissue Res
Involvement of ERS response in corpus luteum development and regression The corpus luteum (CL) is a temporary rhythmic endocrine gland that develops from the ruptured follicle after ovulation during the luteal phase. P4 is produced by the CL and is indispensable for the establishment and maintenance of intrauterine pregnancies in mammals (Bowen-Shauver and Gibori 2004; Choi et al. 2011; Stouffer 2004). The mechanism controlling the regression of the CL is not fully understood. Previous studies have suggested that cellular apoptosis induces the regression of CL (Stocco et al. 2007), and apoptosis is detected in many species during spontaneous and induced CL regression, including cows (Juengel et al. 1993; Rueda et al. 1997), rats (Bowen et al. 1996; Gaytán et al. 2000; Telleria et al. 2001), sheep (Rueda et al. 1995), and humans (Shikone et al. 1996). The death-receptor- and mitochondria-mediated apoptotic systems have been shown to be active in the regression of the CL (Carambula et al. 2003; Dauffenbach et al. 2003; Quirk et al. 2000). In addition, autophagy has also been identified in CL regression (Choi et al. 2011). However, whether ERS induces CL regression remains unknown. UPR signaling pathways have been detected during the CL lifespan in the estrous cycle in bovines, as have the three signaling pathways eIF2α/ATF4/ GADD34 (growth arrest and DNA-damage-inducible gene 34), p90ATF6α (90-kDa ATF6α) / p50ATF6α (90-kDa ATF6α), and IRElα/XBP1. The expression of Grp78/Bip (immunoglobulin heavy chain binding protein in pre-B cells) is increased during the maintenance stage and rapidly decreases at the regression stage. Additionally, UPR genes are found to be involved in luteal phase progression during the estrous cycle, and this finding suggests that Grp78/Bip, ATF6α, and XBP1 act as ER chaperones to initiate CL development and maintenance of the CL (Park et al. 2013). Grp78 might be involved in CL formation by regulating the expression of luteinizing hormone receptor (Kogure et al. 2013). In addition, ERS-mediated apoptosis via the three UPR signaling pathways has been investigated in the CL regression stage. Interestingly, pIRE1α and CHOP have been found to be regulated in both the adaptive response and ERS-mediated apoptosis. During the CL regression stage, increased expression of pJNK and CHOP, two components of ERS-mediated apoptotic cascades, occurs before the increased levels of cleaved caspase-3 are observed (Park et al. 2013). These results are further supported by Park’s data showing that the ERS and UPR are involved in the mouse CL lifespan, and that the secretion of P4 is affected by the UPR (Park et al. 2014). In accordance with Park’s results, our studies suggest that ERS-mediated apoptosis regulates the regression of rat CL through the CHOP pathway and caspase-12 (Yang et al. 2014).
In summary, the development and regression of CL are regulated by ERS, but signaling by the three UPR signaling pathways is not understood. Moreover, whether death-receptor-, mitochondria-, or ERS-mediated apoptotic systems and autophagic cell death interact with each other during CL regression is unknown, and the crosstalk between apoptotic systems and autophagic cell death on the regression of CL is a good topic for further investigation.
Concluding remarks From this historic overview, we have learned that UPR and ERS regulate female mammalian reproduction through the maintenance of cellular homeostasis and the initiation of apoptosis under physiological and pathological conditions. Furthermore, ERS clearly regulates embryo implantation, decidualization, preimplantation embryonic development, follicle atresia, development of placenta, CL development, and regression. The study of the functions of ERS in female mammalian reproduction has provided novel data that can be used further to explore the regulatory mechanism of female mammalian reproduction under physiological and pathological conditions. Such data are important for a better understanding of the regulatory mechanisms of female mammalian reproduction in the presence of ERS, including (1) the infertility caused by disturbing the physiological level of ERS during the female reproductive process; (2) the development of novel targeted drugs that inhibit pathological apoptosis and maintain cellular homeostasis; (3) ERS function and regulation by sex hormones such as E2 and P4; and (4) the relationship between the ERS-response signaling pathway and other pathways and the function of the three UPR signaling pathways in various reproductive process.
References Abraham T, Pin CL, Watson AJ (2012) Embryo collection induces transient activation of XBP1 arm of the ER stress response while embryo vitrification does not. Mol Hum Reprod 18:229–242 Banerjee A, Padh H, Nivsarkar M (2009) Role of the calcium channel in blastocyst implantation: a novel contraceptive target. J Basic Clin Physiol Pharmacol 20:43–53 Banerjee A, Padh H, Nivsarkar M (2011) Hormonal crosstalk with calcium channel blocker during implantation. Syst Biol Reprod Med 57: 186–189 Basar M, Bozkurt I, Guzeloglu-Kayisli O, Sozen B, Tekmen I, Schatz F, Arici A, Lockwood CJ, Kayisli UA (2014) Unfolded protein response prevents blastocyst formation during preimplantation embryo development in vitro. Fertil Steril 102:1777–1784 Bernales S, McDonald KL, Walter P (2006) Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol 4:e423
Cell Tissue Res Bowen JM, Keyes PL, Warren JS, Townson DH (1996) Prolactininduced regression of the rat corpus luteum: expression of monocyte chemoattractant protein-1 and invasion of macrophages. Biol Reprod 54:1120–1127 Bowen-Shauver JM, Gibori G (2004) The corpus luteum of pregnancy. In: Leung PCK, Adashi EY (eds) The ovary. Elseiver/Academic Press, San Diego, pp 201–230 Burton G, Yung HW, Cindrova-Davies T, Charnock-Jones D (2009) Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta 30:43–48 Carambula SF, Pru JK, Lynch MP, Matikainen T, Gonçalves PB, Flavell RA, Tilly JL, Rueda BR (2003) Prostaglandin F2alpha- and FASactivating antibody induced regression of the corpus luteum involves caspase-8 and is defective in caspase-3 deficient mice. Reprod Biol Endocrinol 1:15 Choi JY, Jo MW, Lee EY, Yoon BK, Choi DS (2010) The role of autophagy in follicular development and atresia in rat granulosa cells. Fertil Steril 93:2532–2537 Choi JY, Jo MW, Lee EY, Choi DS (2011) The role of autophagy in corpus luteum regression in the rat. Biol Reprod 85:465–472 Choi JY, Jo MW, Lee EY, Choi DS (2013) AKT is involved in granulosa cell autophagy regulation via mTOR signaling during rat follicular development and atresia. Reproduction 147:73–80 Choi KC, An BS, Yang H, Jeung EB (2011) Regulation and molecular mechanisms of calcium transport genes: do they play a role in calcium transport in the uterine endometrium? J Physiol Pharmacol 62: 499–504 Dai R, Li J, Fu J, Chen Y, Yu L, Zhao X, Qian Y, Zhang H, Chen H, Ren Y, Su B, Luo T, Zhu J, Wang H (2012) Disturbance of Ca2+ homeostasis converts pro-Met into non-canonical tyrosine kinase p190MetNC in response to endoplasmic reticulum stress in MHCC97 cells. J Biol Chem 287:14586–14597 Dauffenbach LM, Khan SM, Yeh J (2003) Corpus luteum regression in the rat in vivo and in vitro studies of apoptotic mechanisms. J Med 34:87–100 Dey S, Lim H, Das SK, Reese J, Paria B, Daikoku T, Wang H (2004) Molecular cues to implantation. Endocr Rev 25:341–373 Ellgaard L, Helenius A (2003) Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol 4:181–191 Fleming J, Fontanier N, Harries D, Rees W (1997) The growth arrest genes gas5, gas6, and CHOP-10 (gadd153) are expressed in the mouse preimplantation embryo. Mol Reprod Dev 48:310–316 Fontanier-Razzaq N, McEvoy TG, Robinson JJ, Rees WD (2001) DNA damaging agents increase gadd153 (CHOP-10) messenger RNA levels in bovine preimplantation embryos cultured in vitro. Biol Reprod 64:1386–1391 Fujita E, Kouroku Y, Isoai A, Kumagai H, Misutani A, Matsuda C, Hayashi YK, Momoi T (2007) Two endoplasmic reticulumassociated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Hum Mol Genet 16:618–629 Fung TS, Liu DX (2014) Coronavirus infection, ER stress, apoptosis and innate immunity. Front Microbiol 5:296 Gao HJ, Zhu YM, He WH, Liu AX, Dong MY, Jin M, Sheng JZ, Huang HF (2012) Endoplasmic reticulum stress induced by oxidative stress in decidual cells: a possible mechanism of early pregnancy loss. Mol Biol Rep 39:9179–9186 Gaytán F, Morales C, Bellido C, Aguilar R, Millán Y, Martín De Las Mulas J, Sánchez-Criado JE (2000) Progesterone on an oestrogen background enhances prolactin-induced apoptosis in regressing corpora lutea in the cyclic rat: possible involvement of luteal endothelial cell progesterone receptors. J Endocrinol 165:715–724 Hao L, Vassena R, Wu G, Han Z, Cheng Y, Latham KE, Sapienza C (2009) The unfolded protein response contributes to preimplantation
mouse embryo death in the DDK syndrome. Biol Reprod 80:944– 953 Hasnain SZ, Lourie R, Das I, Chen AC, McGuckin MA (2012) The interplay between endoplasmic reticulum stress and inflammation. Immunol Cell Biol 90:260–270 Hayashi K, Erikson DW, Tilford SA, Bany BM, Maclean JA, Rucker EB, Johnson GA, Spencer TE (2009) Wnt genes in the mouse uterus: potential regulation of implantation. Biol Reprod 80:989–1000 Hetz C, Thielen P, Matus S, Nassif M, Court F, Kiffin R, Martinez G, Cuervo AM, Brown RH, Glimcher LH (2009) XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev 23:2294–2306 Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K, Tsujimoto Y, Tohyama M (2004) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol 165:347–356 Hong D, Bai YP, Gao HC, Wang X, Li LF, Zhang GG, Hu CP (2014) OxLDL induces endothelial cell apoptosis via the LOX-1-dependent endoplasmic reticulum stress pathway. Atherosclerosis 235:310– 317 Huet-Hudson YM, Andrews GK, Dey SK (1989) Cell type-specific localization of c-myc protein in the mouse uterus: modulation by steroid hormones and analysis of the perimplantation period. Endocrinology 125:1683–1690 Hughes FM, Gorospe WC (1991) Biochemical identification of apoptosis (programmed cell death) in granulosa cells: evidence for a potential mechanism underlying follicular atresia. Endocrinology 129:2415– 2422 Iwawaki T, Akai R, Yamanaka S, Kohno K (2009) Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proc Natl Acad Sci U S A 106:16657–16662 Jheng JR, Ho JY, Horng JT (2014) ER stress, autophagy, and RNA viruses. Front Microbiol 5:388 Jiang JY, Cheung C, Wang Y, Tsang BK (2003) Regulation of cell death and cell survival gene expression during ovarian follicular development and atresia. Front Biosci 8:222–237 Jolly P, Tisdall D, Heath D, Lun S, McNatty K (1994) Apoptosis in bovine granulosa cells in relation to steroid synthesis, cyclic adenosine 3’,5’-monophosphate response to follicle-stimulating hormone and luteinizing hormone, and follicular atresia. Biol Reprod 51:934– 944 Juengel JL, Garverick HA, Johnson AL, Youngquist RS, Smith MF (1993) Apoptosis during luteal regression in cattle. Endocrinology 132:249–254 Jung E, An B, Choi K, Jeung E (2012) Apoptosis- and endoplasmic reticulum stress-related genes were regulated by estrogen and progesterone in the uteri of calbindin-D(9k) and -D(28k) knockout mice. J Cell Biochem 113:194–203 Kaufman RJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13:1211–1233 Kaufman RJ (2002) Orchestrating the unfolded protein response in health and disease. J Clin Invest 110:1389–1398 Kawakami T, Yoshimi M, Kadota Y, Inoue M, Sato M, Suzuki S (2014) Prolonged endoplasmic reticulum stress alters placental morphology and causes low birth weight. Toxicol Appl Pharmacol 275:134–144 Kim JS, Song BS, Lee KS, Kim DH, Kim SU, Choo YK, Chang KT, Koo DB (2012) Tauroursodeoxycholic acid enhances the preimplantation embryo development by reducing apoptosis in pigs. Reprod Domest Anim 47:791–798 Kim SK, Kim YK, Lee AS (1990) Expression of the glucoseregulated proteins (GRP94 and GRP78) in differentiated and undifferentiated mouse embryonic cells and the use of the GRP78 promoter as an expression system in embryonic cells. Differentiation 42:153–159
Cell Tissue Res Kimber SJ, Spanswick C (2000) Blastocyst implantation: the adhesion cascade. Semin Cell Dev Biol 11:77–92 Kogure K, Nakamura K, Ikeda S, Kitahara Y, Nishimura T, Iwamune M, Minegishi T (2013) Glucose-regulated protein, 78-kilodalton is a modulator of luteinizing hormone receptor expression in luteinizing granulosa cells in rats. Biol Reprod 88:8 Koumenis C (2006) ER stress, hypoxia tolerance and tumor progression. Curr Mol Med 6:55–69 Lan X, Jin Y, Yang Y, Lin P, Hu L, Cui C, Li Q, Li X, Wang A (2013) Expression and localization of Luman RNA and protein during mouse implantation and decidualization. Theriogenology 80:138– 144 Lee KY, DeMayo FJ (2004) Animal models of implantation. Reproduction 128:679–695 Lemus L, Goder V (2014) Regulation of endoplasmic reticulumassociated protein degradation (ERAD) by ubiquitin. Cells 3:824– 847 Li B, Yi P, Zhang B, Xu C, Liu Q, Pi Z, Xu X, Chevet E, Liu J (2011) Differences in endoplasmic reticulum stress signalling kinetics determine cell survival outcome through activation of MKP-1. Cell Signal 23:35–45 Li C, Wei J, Li Y, He X, Zhou Q, Yan J, Zhang J, Liu Y, Liu Y, Shu HB (2013) Transmembrane protein 214 (TMEM214) mediates endoplasmic reticulum stress-induced caspase 4 enzyme activation and apoptosis. J Biol Chem 288:17908–17917 Lian IA, Løset M, Mundal SB, Fenstad MH, Johnson MP, Eide IP, Bjørge L, Freed KA, Moses EK, Austgulen R (2011) Increased endoplasmic reticulum stress in decidual tissue from pregnancies complicated by fetal growth restriction with and without pre-eclampsia. Placenta 32:823–829 Lim H, Song H, Paria B, Reese J, Das SK, Dey S (2002) Molecules in blastocyst implantation: uterine and embryonic perspectives. Vitam Horm 64:43–76 Lin P, Yang Y, Li X, Chen F, Cui C, Hu L, Li Q, Liu W, Jin Y (2012) Endoplasmic reticulum stress is involved in granulosa cell apoptosis during follicular atresia in goat ovaries. Mol Reprod Dev 79:423– 432 Lin P, Chen F, Wang N, Wang X, Li X, Zhou J, Jin Y, Wang A (2013) CREBZF expression and hormonal regulation in the mouse uterus. Reprod Biol Endocrinol 11:110 Lin P, Jin Y, Lan X, Yang Y, Chen F, Wang N, Li X, Sun Y, Wang A (2014) GRP78 expression and regulation in the mouse uterus during embryo implantation. J Mol Histol 45:259–268 Lipson KL, Fonseca SG, Urano F (2006) Endoplasmic reticulum stressinduced apoptosis and autoimmunity in diabetes. Curr Mol Med 6: 71–77 Liu AX, He WH, Yin LJ, Lv PP, Zhang Y, Sheng JZ, Leung PC, Huang HF (2011) Sustained endoplasmic reticulum stress as a cofactor of oxidative stress in decidual cells from patients with early pregnancy loss. J Clin Endocrinol Metab 96:E493–E497 Liu XM, Ding GL, Jiang Y, Pan HJ, Zhang D, Wang TT, Zhang RJ, Shu J, Sheng JZ, Huang HF (2012) Down-regulation of S100A11, a calcium-binding protein, in human endometrium may cause reproductive failure. J Clin Endocrinol Metab 97:3672–3683 Liu Z, Yue K, Ma S, Sun X, Tan J (2003) Effects of pregnant mare serum gonadotropin (eCG) on follicle development and granulosa-cell apoptosis in the pig. Theriogenology 59:775–785 Løset M, Mundal SB, Johnson MP, Fenstad MH, Freed KA, Lian IA, Eide IP, Bjørge L, Blangero J, Moses EK, Austgulen R (2011) A transcriptional profile of the decidua in preeclampsia. Am J Obstet Gynecol 204:84.e1-27 Luo S, Mao C, Lee B, Lee AS (2006) GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development. Mol Cell Biol 26:5688– 5697
Malhotra JD, Kaufman RJ (2007) The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18:716–731 Manabe N, Goto Y, Matsuda-Minehata F, Inoue N, Maeda A, Sakamaki K, Miyano T (2004) Regulation mechanism of selective atresia in porcine follicles: regulation of granulosa cell apoptosis during atresia. J Reprod Dev 50:493 Matsuda-Minehata F, Inoue N, Goto Y, Manabe N (2006) The regulation of ovarian granulosa cell death by pro- and anti-apoptotic molecules. J Reprod Dev 52:695–670 Mei Y, Thompson MD, Cohen RA, Tong X (2013) Endoplasmic reticulum stress and related pathological processes. J Pharmacol Biomed Anal 1:1000107 Moenner M, Pluquet O, Bouchecareilh M, Chevet E (2007) Integrated endoplasmic reticulum stress responses in cancer. Cancer Res 67: 10631–10634 Murdoch WJ (1995) Programmed cell death in preovulatory ovine follicles. Biol Reprod 53:8–12 Nakatsukasa K, Kamura T, Brodsky JL (2014) Recent technical developments in the study of ER-associated degradation. Curr Opin Cell Biol 29:82–91 Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26:9220–9231 Oh J, Riek AE, Weng S, Petty M, Kim D, Colonna M, Cella M, BernalMizrachi C (2012) Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation. J Biol Chem 287: 11629–11641 Park HJ, Park SJ, Koo DB, Kong IK, Kim MK, Kim JM, Choi MS, Park YH, Kim SU, Chang KT, Park CK, Chae JI, Lee DS (2013) Unfolding protein response signaling is involved in development, maintenance, and regression of the corpus luteum during the bovine estrous cycle. Biochem Biophys Res Commun 441:344–350 Park HJ, Park SJ, Koo DB, Lee SR, Kong IK, Ryoo JW, Park YI, Chang KT, Lee DS (2014) Progesterone production is affected by unfolded protein response (UPR) signaling during the luteal phase in mice. Life Sci 113:60–67 Park SW, Zhou Y, Lee J, Lee J, Ozcan U (2010) Sarco(endo)plasmic reticulum Ca2+−ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity. Proc Natl Acad Sci U S A 107:19320–19325 Quirk SM, Harman RM, Huber SC, Cowan RG (2000) Responsiveness of mouse corpora luteal cells to Fas antigen (CD95)-mediated apoptosis. Biol Reprod 63:49–56 Rajakoski E (1960) The ovarian follicular system in sexually mature heifers with special reference to seasonal, cyclical, and left-right variations. Acta Endocrinol Suppl (Copenh) 15:836–838 Reid RJ, Heald PJ (1970) Uptake of (3H) leucine into proteins of rat uterus during early pregnancy. Biochim Biophys Acta 204:278–279 Rueda BR, Wegner JA, Marion SL, Wahlen DD, Hoyer PB (1995) Internucleosomal DNA fragmentation in ovine luteal tissue associated with luteolysis: in vivo and in vitro analyses. Biol Reprod 52: 305–312 Rueda BR, Tilly KI, Botros IW, Jolly PD, Hansen TR, Hoyer PB, Tilly JL (1997) Increased bax and interleukin-1beta-converting enzyme messenger ribonucleic acid levels coincide with apoptosis in the bovine corpus luteum during structural regression. Biol Reprod 56:186–193 Salminen A, Kauppinen A, Suuronen T, Kaarniranta K, Ojala J (2009) ER stress in Alzheimer’s disease: a novel neuronal trigger for inflammation and Alzheimer’s pathology. J Neuroinflammation 6:41 Samali A, FitzGerald U, Deegan S, Gupta S (2010) Methods for monitoring endoplasmic reticulum stress and the unfolded protein response. Int J Cell Biol 2010:8303074 Sheveleva EV, Landowski TH, Samulitis BK, Bartholomeusz G, Powis G, Dorr RT (2012) Imexon induces an oxidative endoplasmic
Cell Tissue Res reticulum stress response in pancreatic cancer cells. Mol Cancer Res 210:392–400 Shikone T, Yamoto M, Kokawa K, Yamashita K, Nishimori K, Nakano R (1996) Apoptosis of human corpora lutea during cyclic luteal regression and early pregnancy. J Clin Endocrinol Metab 81:2376–2380 Shimada Y, Kobayashi H, Kawagoe S, Aoki K, Kaneshiro E, Shimizu H, Eto Y, Ida H, Ohashi T (2011) Endoplasmic reticulum stress induces autophagy through activation of p38 MAPK in fibroblasts from Pompe disease patients carrying c. 546G>T mutation. Mol Genet Metab 104:566–573 Siman R, Flood DG, Thinakaran G, Neumar RW (2001) Endoplasmic reticulum stress induced cysteine protease activation in cortical neurons: effect of an Alzheimer’s disease-linked presenilin-1 knock-in mutation. J Biol Chem 276:44736–44743 Simmons D, Kennedy T (2000) Induction of glucose-regulated protein 78 in rat uterine glandular epithelium during uterine sensitization for the decidual cell reaction. Biol Reprod 62:1168–1176 Simon-Szabó L, Kokas M, Mandl J, Kéri G, Csala M (2014) Metformin attenuates palmitate-induced endoplasmic reticulum stress, serine phosphorylation of IRS-1 and apoptosis in rat insulinoma cells. PLoS One 9:e9786816 Stocco C, Telleria C, Gibori G (2007) The molecular control of corpus luteum formation, function, and regression. Endocr Rev 28:117–149 Stouffer RL (2004) The function and regulation of cell populations comprising the corpus luteum during the ovarian cycle. In: Leung PCK, Adashi EY (eds) The ovary. Elseiver/Academic Press, San Diego, pp 169–184 Sugimoto M, Manabe N, Kimura Y, Myoumot A, Imai Y, Ohno H, Miyamoto H (1998) Ultrastructural changes in granulosa cells in porcine antral follicles undergoing atresia indicate apoptotic cell death. J Reprod Dev 144:7–14 Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7: 880–885 Telleria CM, Goyeneche AA, Cavicchia JC, Stati AO, Deis RP (2001) Apoptosis induced by antigestagen RU486 in rat corpus luteum of pregnancy. Endocrine 15:147–155 Terada N, Yamamoto R, Takada T, Miyake T, Terakawa N, Wakimoto H, Taniguchi H, Li W, Kitamura Y, Matsumoto K (1989) Inhibitory effect of progesterone on cell death of mouse uterine epithelium. J Steroid Biochem 33:1091–1096 Tersey SA, Nishiki Y, Templin AT, Cabrera SM, Stull ND, Colvin SC (2012) Islet β-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model. Diabetes 61:818–827 Tirasophon W, Welihinda AA, Kaufman RJ (1998) A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev 12:1812–1824 Todd DJ, Lee A-H, Glimcher LH (2008) The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol 8:663–674 Tomita T (1960) One-side cross sterility between inbred strains of mice. Jpn J Genet 35:291 Tong XM, Lin XN, Song T, Liu L, Zhang SY (2010) Calcium-binding protein S100P is highly expressed during the implantation window in human endometrium. Fertil Steril 94:1510–1518 Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664 Wakasugi N (1973) Studies on fertility of DDK mice: reciprocal crosses between DDK and C57BL/6J strains and experimental transplantation of the ovary. J Reprod Fertil 33:283–291 Wakasugi N (1974) A genetically determined incompatibility system between spermatozoa and eggs leading to embryonic death in mice. J Reprod Fertil 41:85–96
Wang H, Dey SK (2006) Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet 7:185–199 Wang Z, Wang H, Xu ZM, Ji YL, Chen YH, Zhang ZH, Zhang C, Meng XH, Zhao M, Xu DX (2012) Cadmium-induced teratogenicity: association with ROS-mediated endoplasmic reticulum stress in placenta. Toxicol Appl Pharmacol 259:236–247 Wang Z, Jiang C, Chen W, Zhang G, Luo D, Cao Y, Wu J, Ding Y, Liu B (2014) Baicalein induces apoptosis and autophagy via endoplasmic reticulum stress in hepatocellular carcinoma cells. Biomed Res Int 2014:732516 Watson ED, Cross JC (2005) Development of structures and transport functions in the mouse placenta. Physiology (Bethesda) 20:180–193 Wu LL, Dunning KR, Yang X, Russell DL, Lane M, Norman RJ, Robker RL (2010) High-fat diet causes lipotoxicity responses in cumulusoocyte complexes and decreased fertilization rates. Endocrinology 151:5438–5445 Xu C, Bailly-Maitre B, Reed JC (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115:2656–2664 Yang ES, Bae JY, Kim TH, Kim YS, Suk K, Bae YC (2014) Involvement of endoplasmic reticulum stress response in orofacial inflammatory pain. Exp Neurobiol 23:372–380 Yang X, Wu LL, Chura LR, Liang X, Lane M, Norman RJ, Robker RL (2012) Exposure to lipid-rich follicular fluid is associated with endoplasmic reticulum stress and impaired oocyte maturation in cumulus-oocyte complexes. Fertil Steril 97:1438–1443 Yang Y, Lin P, Chen F, Wang A, Lan X, Song Y, Jin Y (2013a) Luman recruiting factor regulates endoplasmic reticulum stress in mouse ovarian granulosa cell apoptosis. Theriogenology 79:633–639 Yang Y, Jin Y, Martyn AC, Lin P, Song Y, Chen F, Hu L, Cui C, Li X, Li Q, Lu R, Wang A (2013b) Expression pattern implicates a potential role for luman recruitment factor in the process of implantation in uteri and development of preimplantation embryos in mice. J Reprod Dev 59:245–251 Yang Y, Sun M, Shan Y, Zheng X, Ma H, Ma W, Wang Z, Pei X, Wang Y (2014) Endoplasmic reticulum stress-mediated apoptotic pathway is involved in corpus luteum regression in rats. Reprod Sci 2014:pii, 1933719114553445 Yorimitsu T, Klionsky DJ (2007) Eating the endoplasmic reticulum: quality control by autophagy. Trends Cell Biol 17:279–285 Yung HW, Calabrese S, Hynx D, Hemmings BA, Cetin I, CharnockJones DS, Burton G (2008) Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction. Am J Pathol 173:451–462 Zhang D, Ma C, Sun X, Xia H, Zhang W (2012) S100P expression in response to sex steroids during the implantation window in human endometrium. Reprod Biol Endocrinol 10:106 Zhang H, Wu F, Kong X, Yang J, Chen H, Deng L, Cheng Y, Ye L, Zhu S, Zhang X, Wang Z, Shi H, Fu X, Li X, Xu H, Lin L, Xiao J (2014) Nerve growth factor improves functional recovery by inhibiting endoplasmic reticulum stress-induced neuronal apoptosis in rats with spinal cord injury. J Transl Med 12:130 Zhang J, Zhu G, Wang X, Xu B, Hu L (2007) Apoptosis and expression of protein TRAIL in granulosa cells of rats with polycystic ovarian syndrome. J Huazhong Univ Sci Technolog Med Sci 27:311–314 Zhang JY, Diao YF, Kim HR, Jin DI (2012) Inhibition of endoplasmic reticulum stress improves mouse embryo development. PLoS One 7:e40433 Zheng YZ, Cao ZG, Hu X, Shao ZM (2014) The endoplasmic reticulum stress markers GRP78 and CHOP predict disease-free survival and responsiveness to chemotherapy in breast cancer. Breast Cancer Res Treat 145:349–358 Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL, Ron D (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12:982–995
REVIEW
The roles of endoplasmic reticulum stress response in female mammalian reproduction Yanzhou Yang 1 & Xiuying Pei 1 & Yaping Jin 3 & Yanrong Wang 1 & Cheng Zhang 2
Received: 1 March 2015 / Accepted: 1 May 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Endoplasmic reticulum stress (ERS) activates a protective pathway, called the unfold protein response, for maintaining cellular homeostasis, but cellular apoptosis is triggered by excessive or persistent ERS. Several recent studies imply that the ERS response might have broader physiological roles in the various reproductive processes of female mammals, including embryo implantation, decidualization, preimplantation embryonic development, follicle atresia, and the development of the placenta. This review summarizes the existing data concerning the molecular and biological roles of the ERS response. The study of the functions of the ERS response in mammalian reproduction might provide novel insights into and an understanding of reproductive cell survival
This work was supported by the Natural Science Foundation of China (no. 81260110); the open project of Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Ningxia Medical University; Beijing Municipal Natural Science Foundation (no. 5142003); and the National Natural Science Foundation of China (no. 31300958). * Yanzhou Yang [email protected] * Cheng Zhang [email protected] 1
Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, Ningxia Medical University, Yinchuan, Ningxia 75004, People’s Republic of China
2
College of Life Science, Capital Normal University, Beijing 100048, Peoples’ Republic of China
3
Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
and apoptosis under physiological and pathological conditions. The ERS response is a novel signaling pathway for reproductive cell survival and apoptosis. Infertility might be a result of disturbing the ERS response during the process of female reproduction. Keywords Endoplasmic reticulum stress response . Follicle atresia . Embryo implantation . Decidualization . Embryonic development . Placental development
Abbreviations ERS Endoplasmic reticulum stress UPR Unfolded protein response Grp78/Bip Glucose-regulated protein 78-kDa/immunoglobulin heavy chain binding protein in pre-B cells ATF6α Activating transcription factor 6α IRE1α Inositol requiring enzyme 1α PERK Pancreatic ER kinase CHOP C/EBP-homologous protein growth arrest and DNA damage-inducible gene 153 GADD153; DNA-damage inducible transcription 3 DDIT3 JNK c-Jun N-terminal kinase eIF2α Eukaryotic initiation factor 2α Xbp1(U) Unspliced X-box binding protein Xbp1(S) Spliced X-box binding protein
Introduction The endoplasmic reticulum (ER) is an important organelle for protein folding, transport, and synthesis. However, the microenvironment of the ER can be disturbed by the depletion of Ca2+, hypoxia, and the dysfunction of N-terminal glycosylation, causing ER stress (ERS; Kaufman 1999; Koumenis
Cell Tissue Res
2006). As a consequence of ERS, unfolded and misfolded proteins accumulate in the ER. When this occurs, the ERS response (unfold protein response, UPR) is initiated to relieve ERS and to promote cell survival (Kaufman 2002; Xu et al. 2005; Yang et al. 2014). Three signaling transduction pathways are involved in the UPR: (1) PERK (pancreatic ER kinase)/eIF2α (eukaryotic initiation factor 2α)/ATF4 (activating transcription factor 4), (2) IRElα (inositol requiring enzyme 1α)/XBP-1 (X-box-binding protein), and (3) ATF6α (activating transcription factor 6α; Fung and Liu 2014; Jheng et al. 2014; Mei et al. 2013). Through the UPR, the ER load is relieved by three processes, as follows: (1) a reduction of the entry of newly synthesized proteins into the ER through attenuating protein translation; (2) an increase in the proteinfolding capacity through upregulating ER gene expression; and (3) a degradation of misfolded and unfolded proteins through ER-associated degradation (ERAD) and lysosomemediated autophagy (Fig. 1; Ellgaard and Helenius 2003; Lemus and Goder 2014; Yorimitsu and Klionsky 2007). The misfolded and unfolded proteins are mainly degraded by ERAD through the ubiquitin-proteasome system (termed as ERAD I; Fujita et al. 2007; Nakatsukasa et al. 2014), but lysosome-mediated autophagy is triggered when the ERAD is impaired, and therefore, lysosome-mediated autophagy has been referred to as an ERAD II pathway (Fujita et al. 2007; Hetz et al. 2009). However, when the UPR fails to deal with the unfolded and misfolded proteins, cellular apoptosis is triggered by excessive or persistent ERS (Malhotra and Kaufman 2007; Oh et al. 2012; Samali et al. 2010; Sheveleva et al. 2012; Tersey et al. 2012; Xu et al. 2005) through the activation of the CHOP (C/EBP-homologous protein; growth arrest and DNA damage-inducible gene 153, GADD153; DNA—damage inducible transcription 3, DDIT3), c-Jun N-terminal kinase (JNK), and caspase-dependent pathways, with caspase-4 in human and caspase-12 in rodents (Fig. 1; Hitomi et al. 2004; Li et al. 2011; Siman et al. 2001; Szegezdi et al. 2006; Urano et al. 2000). Glucose-regulated protein 78-kDa (GRP78, also known as Bip) is an ER chaperone that interacts with PERK, IRElα, and ATF6α in the ER membrane, but Grp78 dislocates from PERK, IRElα, and ATF6α and enters the ER lumen in the presence of the ERS response. The function of Grp78 is antiapoptotic during the ERS response (Zheng et al. 2014); CHOP (Zhang et al. 2014; Zheng et al. 2014; Zinszner et al. 1998), JNK (Simon-Szabó et al. 2014; Wang et al. 2014), and caspase-4/12 (Hong et al. 2014; Zhang et al. 2014) are proapoptosis and activate ERS-mediated apoptosis. CHOP is downstream of three UPR signaling pathways, and one or more is UPR-signaling-dependent. JNK is IRElα-signalingdependent. Caspase-4/12 is independent of the three UPR signaling pathways. JNK is phosphorylated and caspase-4/12 is cleaved when apoptosis is triggered by ERS (Fig. 1; Fung and Liu 2014; Jheng et al. 2014; Mei et al. 2013).
Previous studies have reported that the ERS response occurs in several physiological and pathological process, including the immune response (Hasnain et al. 2012; Todd et al. 2008), inflammation (Hasnain et al. 2012), autophagy (Bernales et al. 2006; Ogata et al. 2006; Shimada et al. 2011), and metabolic diseases such as diabetes (Hasnain et al. 2012; Lipson et al. 2006), bone and joint diseases (Hasnain et al. 2012), neurogenic diseases such as Alzheimer’s disease (Salminen et al. 2009), cancer (Moenner et al. 2007), and viral replication (Li et al. 2013). In addition, some recent research has suggested that the ERS response is also involved in female reproduction. This review examines the functions of ERS in mammalian female reproduction. The study of the ERS response function in reproduction should broaden our understanding of the way that reproductive cells and tissues maintain their microenvironment and might reveal novel signaling pathways that regulate apoptosis in reproductive tissues under physiological and pathological conditions.
Involvement of ERS response in follicle atresia Follicular atresia occurs via apoptosis of the ovarian granulosa cells (Hughes and Gorospe 1991; Rajakoski 1960) in mice (Hughes and Gorospe 1991), cows (Jolly et al. 1994), ewes (Murdoch 1995), and pigs (Liu et al. 2003; Sugimoto et al. 1998), and infertility is caused by excessive follicle atresia. Apoptotic signaling pathways mediated by death-receptorand mitochondria-mediated type I programmed cell death (also called apoptotic cell death) systems are active in granulosa cells in mammalian ovaries (Jiang et al. 2003; Manabe et al. 2004; Matsuda-Minehata et al. 2006). In addition, previous studies have suggested that follicle atresia is induced by autophagy, which is type II programmed cell death (also called autophagic cell death; Choi et al. 2010, 2013). Therefore, follicle atresia is regulated by apoptotic and autophagic cell death, but whether apoptotic and autophagic cell death interact with each other during follicle atresia remains unknown. Cellular apoptosis is initiated by excessive or persistent ERS. GRP78 is an ER chaperone with multiple functional roles in protein processing and cellular protection (Kogure et al. 2013). The expression of Grp78 in ovarian granulosa cells implies that ovarian granulosa cell apoptosis is induced by ERS and that ERS is a signaling pathway in goat ovarian granulosa cell apoptosis and follicle atresia (Lin et al. 2012). Compared with normal goat follicles, Grp78 and CHOP are remarkably upregulated in apoptotic granulosa cells of the early atretic follicle, and Grp78 is downregulated, whereas CHOP is further upregulated, during the process of atresia. These data are further supported by cell culture experiments in vitro. ERS is induced by the ERS inducer tunicamycin. In accordance with Lin’s results, Yang’s research has further suggested that the apoptosis in mouse ovarian granulosa cells is
Cell Tissue Res
Fig. 1 Endoplasmic reticulum (ER) stress (ERS) and unfold protein response (UPR) signaling pathway. Bip (also called glucose-regulated protein 78-kDa) combines with activating transcription factor 6 (ATF6), inositol requiring enzyme 1α (IRE1α), and pancreatic ER kinase (PERK) in the ER membrane. Bip translocates from the membrane to the lumen in response to ERS. ATF6 translocates from the ER into Golgi body and is processed by Site-1 (S1P) and Site-2 protease (S2P). IRE1α and PERK are activated by phosphorylation (p). The three UPR signaling pathways
(yellow arrows), namely C/EBP-homologous protein; growth arrest and DNA damage-inducible gene 153, GADD153; DNA—damage inducible transcription 3, DDIT3 (CHOP), caspase-12, and c-Jun N-terminal kinase (JNK), are activated to relieve the ER load by (black boxes) increasing the protein-folding capacity, attenuating protein translation, and degrading unfolded and misfolded protein (Xbp1(U) unspliced X-box binding protein, Xbp1(S) spliced X-box binding protein, eIF2α eukaryotic initiation factor 2α, ERAD ER-associated degradation)
triggered by ERS (Yang et al. 2013a, b). In addition, ovarian granulosa cell apoptosis is triggered by ERS, under conditions of obesity and polycystic ovary syndrome (PCOS), and ERSmediated apoptosis might be a potential pathogenic mechanism of obesity and PCOS (Wu et al. 2010; Zhang et al. 2007). Mouse cumulus-oocyte complexes have been cultured in vitro and exposed to lipid-rich follicular fluid, causing the induction of ERS and the impairment of oocyte maturation, unlike complexes exposed to lipid-poor follicular fluid and complexes matured in vivo (Yang et al. 2012). Therefore, ERS is a novel mechanism involved in ovarian granulosa cell apoptosis and follicle atresia caused by physiological and pathological conditions. The way that ERS affects the three UPR signaling pathways in granulosa cell apoptosis is not fully understood. Whether the function of ERS in granulosa cell apoptosis is closely related to the death receptor, mitochondria-mediated apoptosis, and autophagymediated granulosa cell death is unknown; this potential mechanism needs to be explored further.
Involvement of ERS response in preimplantation embryonic development The ERS response is an evolutionarily conserved mechanism and is indispensable for preimplantation embryonic development. Grp78 is minimally detected in mouse zygotes, weakly detected from the two-cell to the morula stage, but strongly detected in the blastocyst, indicating that Grp78 regulates the development of the blastocyst (Kim et al. 1990). Further, Grp78−/− (homozygous knockout) embryos are unable to survive beyond the peri-implantation stage and exhibit periimplantation lethality. These embryos do not grow in culture and exhibit increased apoptosis in the inner cell mass and reduced proliferation (Luo et al. 2006). Therefore, Grp78 is essential for embryonic growth and protects the inner cell mass from apoptosis. In addition, CHOP is only detected before the eight-cell stage in vivo but has been found in the zygote to blastocyst stages when the embryo is cultured in KSOM media in vitro
Cell Tissue Res
(Fleming et al. 1997). In cow embryos cultured in vitro in the presence of a DNA-damaging reagent, CHOP expression increases remarkably in response to ERS (Fontanier-Razzaq et al. 2001). Additionally, the existence of other ERS response-related proteins, such as Luman recruiting factor (Yang et al. 2013a, b) and SMILE/Zhangfei (Lin et al. 2013), in the zygote to blastocyst stages is further evidence that preimplantation embryonic development is regulated by ERS response. Preimplantation embryonic apoptosis and developmental arrest frequently occur during embryo culture in vitro and embryonic cryopreservation, and the survival rates are low. However, the mechanism of embryonic apoptosis and developmental arrest remain unknown. The mechanism by which the embryo adapts to the culture microenvironment in vitro is also unknown. The hypothesis that the ERS response regulates early embryonic development stems from several findings. When preimplantation pig embryos are cultured in vitro in the presence of the ERS inducer tunicamycin, the apoptotic rate is significantly higher than that of the control, and the capacity to develop into a blastocyst is significantly lower than that of the control. In addition, the XBP-1 mRNA level is remarkably upregulated in the experimental group compared with the control. In contrast, when the ERS inhibitor TUDCA (tauroursodeoxycholic acid) is added, the capacity to develop into a blastocyst is significantly higher than that of the control. Therefore, TUDCA protects preimplantation embryos from apoptosis induced by ERS (Kim et al. 2012). Indeed, inhibition of ERS improves mouse embryonic development and decreases ERS-induced apoptosis (Zhang et al. 2012). Furthermore, the consistent results suggest that the UPR prevents blastocyst formation during preimplantation embryo development in vitro, and that TUDCA reverses this outcome (Basar et al. 2014). Embryonic cryopreservation is a common assistedreproduction technique, but the effect of vitrification on preimplantation embryonic development is not clear. Whether ERS and the UPR are initiated during standard embryonic treatments, including embryo collection, culture, and vitrification, is unknown. Abraham’s studies have suggested that the main ERS response pathway is initiated at all stages of the preimplantation embryo, especially at the eight-cell, morula, and blastocyst stages (Abraham et al. 2012). Moreover, the IRE1α signaling pathway is activated in freshly collected embryos but is not initiated by embryonic vitrification (Abraham et al. 2012). DDK syndrome is a polar early embryonic lethal phenotype that occurs when DDK females are mated with males of other inbred mouse strains, and lethality occurs during the transformation from morula to blastocyst (Tomita 1960; Wakasugi 1973, 1974). Analysis of the gene expression in morulae of DDK×DDK (high survival
rate) and DDK×C57BL/6 (low survival rate) crosses have revealed that many UPR genes are upregulated, Grp78 accumulates in the ER, the structure of the ER is abnormal, and the expression of the ERS-response-related proteins HERPUD1 (homocysteine-inducible, ER stress-inducible, ubiquitin-like domain member 1) and ATF4 are upregulated in the DDK×C57BL/6 embryo. These results suggest that DDK syndrome, which causes early embryonic lethality, is controlled by an ERS response signaling pathway (Hao et al. 2009). In summary, the ERS response maintains preimplantation embryonic development and adaptation to the microenvironment in vivo and in vitro, but ERS-associated apoptosis is triggered by excessive ERS, making it a key component of early embryonic lethality, embryonic apoptosis, and developmental arrest.
Involvement of ERS response in embryo implantation and decidualization Embryo implantation is a critical step in female mammalian reproduction and occurs through an intricate interaction between the activated blastocyst and receptive uterus (Dey et al. 2004; Wang and Dey 2006). The embryo trophectoderm initiates attachment to the uterine epithelium and then invades the endometrium during implantation (Hayashi et al. 2009; Kimber and Spanswick 2000; Lee and DeMayo 2004). Estrogen (E2) and progesterone (P4) are indispensable for the implantation process (Hayashi et al. 2009; Huet-Hudson et al. 1989). Understanding of the complete mechanism of embryonic implantation is lacking. Many ERS response genes and proteins are upregulated during embryo implantation, indicating that the ERS response is essential for the embryo implantation. The transcript of Grp78 is significantly increased in the pregnant mouse uterus on day 5 when embryo implantation occurs, and the function of Grp78 is regulated by E2 (Simmons and Kennedy 2000). Consistent with the Grp78 mRNA level, Grp78 protein significantly increases in the pregnant mouse uterus on day 5, especially in the implantation site (Lin et al. 2014; Reid and Heald 1970), and these results suggest that increased Grp78 in the pregnant mouse uterus plays important roles in embryo implantation through the UPR and ERS. Additionally, the upregulation of the calcium-binding protein S100P in the human uterine epithelium during embryo implantation (Tong et al. 2010; Zhang et al. 2012), the embryo implantation failure caused by the downregulation of the calcium-binding protein S100A11 (Liu et al. 2012), and the abundant expression of calcium-transport genes in reproductive tissues in a
Cell Tissue Res
distinct manner (Choi et al. 2011) suggest that calcium regulates embryo implantation, and that calcium-channel blockers might provide new targets for female contraceptives (Banerjee et al. 2009, 2011). Nevertheless, ERS is triggered by a disturbance of Ca2+ homeostasis, and ERS and the UPR play an important role in the maintenance of Ca2+ homeostasis (Dai et al. 2012; Park et al. 2010). Therefore, our limited knowledge leads us to speculate that calcium regulates embryo implantation through ERS and the UPR. Indeed, the expression of ERS genes in the uterus is changed in calbindin-D(9 k) and -D(28 k) knockout mice (Jung et al. 2012). A previous study has suggested that the cellular apoptosis and the cellular homeostasis in the uterus are regulated by the ERS response. E2 and P4 regulate cellular apoptosis in the uterus. E2 induces apoptosis of the uterine epithelium, whereas P4 represses it (Terada et al. 1989). P4 is induced by the ERS response pathway (Jung et al. 2012). Following implantation, extensive proliferation and differentiation of stromal cells into decidual cells occurs to establish a vascular relationship with maternal tissue (Dey et al. 2004; Hayashi et al. 2009; Lim et al. 2002; Wang and Dey 2006). In abortive uterine decidual cells, ERS is caused by increased oxidative stress, suggesting that ERS and oxidative stress play important roles in early pregnancy loss (Gao et al. 2012; Liu et al. 2011). However, regardless of whether ERS is initiated under physiological conditions or not, previous studies have suggested that, compared with the control, the expression of Grp78 in mouse decidual uterus does not change significantly (Simmons and Kennedy 2000), suggesting that ERS might not be involved in decidualization. In contrast, our previous studies have suggested that Grp78 is remarkably upregulated in pregnant mouse uteri at day 5 (embryo implantation has occurred) and days 6–8 (decidualization; Lin et al. 2014). These results indicate that ERS might be involved in decidualization. Our research has revealed that the ERS-response-regulated protein Luman (Lan et al. 2013) and Luman recruiting factor (Yang et al. 2013a, b) are upregulated in pregnant mouse uteri during day 5 and days 6–8 and further suggests that ERS regulates embryonic implantation and decidualization. Another ERSresponse-associated protein, SMILE/Zhangfei, is also detectable in implantation sites but not in inter-implantation sites (Lin et al. 2013). These results further imply that the ERS response regulates embryo implantation and decidualization. In summary, physiological levels of ERS are involved in embryo implantation and decidualization, and implantation failure and early pregnancy loss are caused by abnormal ERS. These data provide novel insight into the mechanism of implantation failure and early pregnancy loss.
Involvement of ERS response in placenta function The placenta is indispensable for the embryo, and fetal growth restriction, fetal death, and birth defects are caused by placental malfunction (Watson and Cross 2005). Recent studies have suggested that increased ERS is closely related to placental development and fetal growth restriction (Iwawaki et al. 2009; Lian et al. 2011; Yung et al. 2008). Administration of CdCl2 to a pregnant mouse on day 9 (4.5 mg/kg) via intraperitoneal injection resulted in placental cell proliferation inhibition and apoptosis through the upregulation of Grp78 and other ERS-response-induced molecular chaperones. eIF2α of the PERK pathway was phosphorylated, and CHOP was upregulated (Wang et al. 2012). In the fetal growth-restricted placenta, ERS is significantly increased. Decreased placental cell proliferation and apoptosis and increased ERS might be the main reasons for the decreased placental growth (Burton et al. 2009; Yung et al. 2008). In addition, active PERK-peIF2α and ATF6α signal pathways have been detected, and XBP1(U) (unspliced Xbox-binding protein) and ATF6α protein remarkably increase in the fetal growth-restricted placenta (Lian et al. 2011). Compared with the decidual tissue of the normal pregnant placenta, many ERS response genes are significantly upregulated in placental decidual tissue in the case of preeclampsia (Løset et al. 2011). IRE1α is an important target gene in the ERS response pathway, and the widespread expression of IRE1α in the mouse is indispensable for female mammalian development (Tirasophon et al. 1998; Urano et al. 2000). IRE1α, Grp78, and EDEM (ER-degradation enhancing α-mannosidase-like protein) are strongly expressed in the mouse placenta, and XBP1(S) (spliced X-box-binding protein) mRNA and the active form of the PERK-peIF2a and ATF6α proteins are also detected in the placenta (Iwawaki et al. 2009). In addition, XBP1 has been shown to be essential for mouse placental development (Iwawaki et al. 2009). These results suggest that ERS is indispensable for the growth of the placenta. However, IRE1α knockout mice die on day 12.5 as a result of impaired function of vascular endothelial growth factor and the placental labyrinth layer. Furthermore, similar results have suggested that the placental morphology is impaired and low birth weight is caused by prolonged ERS through a decrease in the expression of vascular endothelial growth factor receptors 1 and 2 (Kawakami et al. 2014). These results suggest that physiological intercommunication occurs between placental angiogenesis and the ERS response (Iwawaki et al. 2009). In summary, these data suggest that ERS is mediated in placental development, but that the function of the placenta is impaired by both loss of ERS response and excessive ERS.
Cell Tissue Res
Involvement of ERS response in corpus luteum development and regression The corpus luteum (CL) is a temporary rhythmic endocrine gland that develops from the ruptured follicle after ovulation during the luteal phase. P4 is produced by the CL and is indispensable for the establishment and maintenance of intrauterine pregnancies in mammals (Bowen-Shauver and Gibori 2004; Choi et al. 2011; Stouffer 2004). The mechanism controlling the regression of the CL is not fully understood. Previous studies have suggested that cellular apoptosis induces the regression of CL (Stocco et al. 2007), and apoptosis is detected in many species during spontaneous and induced CL regression, including cows (Juengel et al. 1993; Rueda et al. 1997), rats (Bowen et al. 1996; Gaytán et al. 2000; Telleria et al. 2001), sheep (Rueda et al. 1995), and humans (Shikone et al. 1996). The death-receptor- and mitochondria-mediated apoptotic systems have been shown to be active in the regression of the CL (Carambula et al. 2003; Dauffenbach et al. 2003; Quirk et al. 2000). In addition, autophagy has also been identified in CL regression (Choi et al. 2011). However, whether ERS induces CL regression remains unknown. UPR signaling pathways have been detected during the CL lifespan in the estrous cycle in bovines, as have the three signaling pathways eIF2α/ATF4/ GADD34 (growth arrest and DNA-damage-inducible gene 34), p90ATF6α (90-kDa ATF6α) / p50ATF6α (90-kDa ATF6α), and IRElα/XBP1. The expression of Grp78/Bip (immunoglobulin heavy chain binding protein in pre-B cells) is increased during the maintenance stage and rapidly decreases at the regression stage. Additionally, UPR genes are found to be involved in luteal phase progression during the estrous cycle, and this finding suggests that Grp78/Bip, ATF6α, and XBP1 act as ER chaperones to initiate CL development and maintenance of the CL (Park et al. 2013). Grp78 might be involved in CL formation by regulating the expression of luteinizing hormone receptor (Kogure et al. 2013). In addition, ERS-mediated apoptosis via the three UPR signaling pathways has been investigated in the CL regression stage. Interestingly, pIRE1α and CHOP have been found to be regulated in both the adaptive response and ERS-mediated apoptosis. During the CL regression stage, increased expression of pJNK and CHOP, two components of ERS-mediated apoptotic cascades, occurs before the increased levels of cleaved caspase-3 are observed (Park et al. 2013). These results are further supported by Park’s data showing that the ERS and UPR are involved in the mouse CL lifespan, and that the secretion of P4 is affected by the UPR (Park et al. 2014). In accordance with Park’s results, our studies suggest that ERS-mediated apoptosis regulates the regression of rat CL through the CHOP pathway and caspase-12 (Yang et al. 2014).
In summary, the development and regression of CL are regulated by ERS, but signaling by the three UPR signaling pathways is not understood. Moreover, whether death-receptor-, mitochondria-, or ERS-mediated apoptotic systems and autophagic cell death interact with each other during CL regression is unknown, and the crosstalk between apoptotic systems and autophagic cell death on the regression of CL is a good topic for further investigation.
Concluding remarks From this historic overview, we have learned that UPR and ERS regulate female mammalian reproduction through the maintenance of cellular homeostasis and the initiation of apoptosis under physiological and pathological conditions. Furthermore, ERS clearly regulates embryo implantation, decidualization, preimplantation embryonic development, follicle atresia, development of placenta, CL development, and regression. The study of the functions of ERS in female mammalian reproduction has provided novel data that can be used further to explore the regulatory mechanism of female mammalian reproduction under physiological and pathological conditions. Such data are important for a better understanding of the regulatory mechanisms of female mammalian reproduction in the presence of ERS, including (1) the infertility caused by disturbing the physiological level of ERS during the female reproductive process; (2) the development of novel targeted drugs that inhibit pathological apoptosis and maintain cellular homeostasis; (3) ERS function and regulation by sex hormones such as E2 and P4; and (4) the relationship between the ERS-response signaling pathway and other pathways and the function of the three UPR signaling pathways in various reproductive process.
References Abraham T, Pin CL, Watson AJ (2012) Embryo collection induces transient activation of XBP1 arm of the ER stress response while embryo vitrification does not. Mol Hum Reprod 18:229–242 Banerjee A, Padh H, Nivsarkar M (2009) Role of the calcium channel in blastocyst implantation: a novel contraceptive target. J Basic Clin Physiol Pharmacol 20:43–53 Banerjee A, Padh H, Nivsarkar M (2011) Hormonal crosstalk with calcium channel blocker during implantation. Syst Biol Reprod Med 57: 186–189 Basar M, Bozkurt I, Guzeloglu-Kayisli O, Sozen B, Tekmen I, Schatz F, Arici A, Lockwood CJ, Kayisli UA (2014) Unfolded protein response prevents blastocyst formation during preimplantation embryo development in vitro. Fertil Steril 102:1777–1784 Bernales S, McDonald KL, Walter P (2006) Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol 4:e423
Cell Tissue Res Bowen JM, Keyes PL, Warren JS, Townson DH (1996) Prolactininduced regression of the rat corpus luteum: expression of monocyte chemoattractant protein-1 and invasion of macrophages. Biol Reprod 54:1120–1127 Bowen-Shauver JM, Gibori G (2004) The corpus luteum of pregnancy. In: Leung PCK, Adashi EY (eds) The ovary. Elseiver/Academic Press, San Diego, pp 201–230 Burton G, Yung HW, Cindrova-Davies T, Charnock-Jones D (2009) Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta 30:43–48 Carambula SF, Pru JK, Lynch MP, Matikainen T, Gonçalves PB, Flavell RA, Tilly JL, Rueda BR (2003) Prostaglandin F2alpha- and FASactivating antibody induced regression of the corpus luteum involves caspase-8 and is defective in caspase-3 deficient mice. Reprod Biol Endocrinol 1:15 Choi JY, Jo MW, Lee EY, Yoon BK, Choi DS (2010) The role of autophagy in follicular development and atresia in rat granulosa cells. Fertil Steril 93:2532–2537 Choi JY, Jo MW, Lee EY, Choi DS (2011) The role of autophagy in corpus luteum regression in the rat. Biol Reprod 85:465–472 Choi JY, Jo MW, Lee EY, Choi DS (2013) AKT is involved in granulosa cell autophagy regulation via mTOR signaling during rat follicular development and atresia. Reproduction 147:73–80 Choi KC, An BS, Yang H, Jeung EB (2011) Regulation and molecular mechanisms of calcium transport genes: do they play a role in calcium transport in the uterine endometrium? J Physiol Pharmacol 62: 499–504 Dai R, Li J, Fu J, Chen Y, Yu L, Zhao X, Qian Y, Zhang H, Chen H, Ren Y, Su B, Luo T, Zhu J, Wang H (2012) Disturbance of Ca2+ homeostasis converts pro-Met into non-canonical tyrosine kinase p190MetNC in response to endoplasmic reticulum stress in MHCC97 cells. J Biol Chem 287:14586–14597 Dauffenbach LM, Khan SM, Yeh J (2003) Corpus luteum regression in the rat in vivo and in vitro studies of apoptotic mechanisms. J Med 34:87–100 Dey S, Lim H, Das SK, Reese J, Paria B, Daikoku T, Wang H (2004) Molecular cues to implantation. Endocr Rev 25:341–373 Ellgaard L, Helenius A (2003) Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol 4:181–191 Fleming J, Fontanier N, Harries D, Rees W (1997) The growth arrest genes gas5, gas6, and CHOP-10 (gadd153) are expressed in the mouse preimplantation embryo. Mol Reprod Dev 48:310–316 Fontanier-Razzaq N, McEvoy TG, Robinson JJ, Rees WD (2001) DNA damaging agents increase gadd153 (CHOP-10) messenger RNA levels in bovine preimplantation embryos cultured in vitro. Biol Reprod 64:1386–1391 Fujita E, Kouroku Y, Isoai A, Kumagai H, Misutani A, Matsuda C, Hayashi YK, Momoi T (2007) Two endoplasmic reticulumassociated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Hum Mol Genet 16:618–629 Fung TS, Liu DX (2014) Coronavirus infection, ER stress, apoptosis and innate immunity. Front Microbiol 5:296 Gao HJ, Zhu YM, He WH, Liu AX, Dong MY, Jin M, Sheng JZ, Huang HF (2012) Endoplasmic reticulum stress induced by oxidative stress in decidual cells: a possible mechanism of early pregnancy loss. Mol Biol Rep 39:9179–9186 Gaytán F, Morales C, Bellido C, Aguilar R, Millán Y, Martín De Las Mulas J, Sánchez-Criado JE (2000) Progesterone on an oestrogen background enhances prolactin-induced apoptosis in regressing corpora lutea in the cyclic rat: possible involvement of luteal endothelial cell progesterone receptors. J Endocrinol 165:715–724 Hao L, Vassena R, Wu G, Han Z, Cheng Y, Latham KE, Sapienza C (2009) The unfolded protein response contributes to preimplantation
mouse embryo death in the DDK syndrome. Biol Reprod 80:944– 953 Hasnain SZ, Lourie R, Das I, Chen AC, McGuckin MA (2012) The interplay between endoplasmic reticulum stress and inflammation. Immunol Cell Biol 90:260–270 Hayashi K, Erikson DW, Tilford SA, Bany BM, Maclean JA, Rucker EB, Johnson GA, Spencer TE (2009) Wnt genes in the mouse uterus: potential regulation of implantation. Biol Reprod 80:989–1000 Hetz C, Thielen P, Matus S, Nassif M, Court F, Kiffin R, Martinez G, Cuervo AM, Brown RH, Glimcher LH (2009) XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev 23:2294–2306 Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K, Tsujimoto Y, Tohyama M (2004) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol 165:347–356 Hong D, Bai YP, Gao HC, Wang X, Li LF, Zhang GG, Hu CP (2014) OxLDL induces endothelial cell apoptosis via the LOX-1-dependent endoplasmic reticulum stress pathway. Atherosclerosis 235:310– 317 Huet-Hudson YM, Andrews GK, Dey SK (1989) Cell type-specific localization of c-myc protein in the mouse uterus: modulation by steroid hormones and analysis of the perimplantation period. Endocrinology 125:1683–1690 Hughes FM, Gorospe WC (1991) Biochemical identification of apoptosis (programmed cell death) in granulosa cells: evidence for a potential mechanism underlying follicular atresia. Endocrinology 129:2415– 2422 Iwawaki T, Akai R, Yamanaka S, Kohno K (2009) Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proc Natl Acad Sci U S A 106:16657–16662 Jheng JR, Ho JY, Horng JT (2014) ER stress, autophagy, and RNA viruses. Front Microbiol 5:388 Jiang JY, Cheung C, Wang Y, Tsang BK (2003) Regulation of cell death and cell survival gene expression during ovarian follicular development and atresia. Front Biosci 8:222–237 Jolly P, Tisdall D, Heath D, Lun S, McNatty K (1994) Apoptosis in bovine granulosa cells in relation to steroid synthesis, cyclic adenosine 3’,5’-monophosphate response to follicle-stimulating hormone and luteinizing hormone, and follicular atresia. Biol Reprod 51:934– 944 Juengel JL, Garverick HA, Johnson AL, Youngquist RS, Smith MF (1993) Apoptosis during luteal regression in cattle. Endocrinology 132:249–254 Jung E, An B, Choi K, Jeung E (2012) Apoptosis- and endoplasmic reticulum stress-related genes were regulated by estrogen and progesterone in the uteri of calbindin-D(9k) and -D(28k) knockout mice. J Cell Biochem 113:194–203 Kaufman RJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13:1211–1233 Kaufman RJ (2002) Orchestrating the unfolded protein response in health and disease. J Clin Invest 110:1389–1398 Kawakami T, Yoshimi M, Kadota Y, Inoue M, Sato M, Suzuki S (2014) Prolonged endoplasmic reticulum stress alters placental morphology and causes low birth weight. Toxicol Appl Pharmacol 275:134–144 Kim JS, Song BS, Lee KS, Kim DH, Kim SU, Choo YK, Chang KT, Koo DB (2012) Tauroursodeoxycholic acid enhances the preimplantation embryo development by reducing apoptosis in pigs. Reprod Domest Anim 47:791–798 Kim SK, Kim YK, Lee AS (1990) Expression of the glucoseregulated proteins (GRP94 and GRP78) in differentiated and undifferentiated mouse embryonic cells and the use of the GRP78 promoter as an expression system in embryonic cells. Differentiation 42:153–159
Cell Tissue Res Kimber SJ, Spanswick C (2000) Blastocyst implantation: the adhesion cascade. Semin Cell Dev Biol 11:77–92 Kogure K, Nakamura K, Ikeda S, Kitahara Y, Nishimura T, Iwamune M, Minegishi T (2013) Glucose-regulated protein, 78-kilodalton is a modulator of luteinizing hormone receptor expression in luteinizing granulosa cells in rats. Biol Reprod 88:8 Koumenis C (2006) ER stress, hypoxia tolerance and tumor progression. Curr Mol Med 6:55–69 Lan X, Jin Y, Yang Y, Lin P, Hu L, Cui C, Li Q, Li X, Wang A (2013) Expression and localization of Luman RNA and protein during mouse implantation and decidualization. Theriogenology 80:138– 144 Lee KY, DeMayo FJ (2004) Animal models of implantation. Reproduction 128:679–695 Lemus L, Goder V (2014) Regulation of endoplasmic reticulumassociated protein degradation (ERAD) by ubiquitin. Cells 3:824– 847 Li B, Yi P, Zhang B, Xu C, Liu Q, Pi Z, Xu X, Chevet E, Liu J (2011) Differences in endoplasmic reticulum stress signalling kinetics determine cell survival outcome through activation of MKP-1. Cell Signal 23:35–45 Li C, Wei J, Li Y, He X, Zhou Q, Yan J, Zhang J, Liu Y, Liu Y, Shu HB (2013) Transmembrane protein 214 (TMEM214) mediates endoplasmic reticulum stress-induced caspase 4 enzyme activation and apoptosis. J Biol Chem 288:17908–17917 Lian IA, Løset M, Mundal SB, Fenstad MH, Johnson MP, Eide IP, Bjørge L, Freed KA, Moses EK, Austgulen R (2011) Increased endoplasmic reticulum stress in decidual tissue from pregnancies complicated by fetal growth restriction with and without pre-eclampsia. Placenta 32:823–829 Lim H, Song H, Paria B, Reese J, Das SK, Dey S (2002) Molecules in blastocyst implantation: uterine and embryonic perspectives. Vitam Horm 64:43–76 Lin P, Yang Y, Li X, Chen F, Cui C, Hu L, Li Q, Liu W, Jin Y (2012) Endoplasmic reticulum stress is involved in granulosa cell apoptosis during follicular atresia in goat ovaries. Mol Reprod Dev 79:423– 432 Lin P, Chen F, Wang N, Wang X, Li X, Zhou J, Jin Y, Wang A (2013) CREBZF expression and hormonal regulation in the mouse uterus. Reprod Biol Endocrinol 11:110 Lin P, Jin Y, Lan X, Yang Y, Chen F, Wang N, Li X, Sun Y, Wang A (2014) GRP78 expression and regulation in the mouse uterus during embryo implantation. J Mol Histol 45:259–268 Lipson KL, Fonseca SG, Urano F (2006) Endoplasmic reticulum stressinduced apoptosis and autoimmunity in diabetes. Curr Mol Med 6: 71–77 Liu AX, He WH, Yin LJ, Lv PP, Zhang Y, Sheng JZ, Leung PC, Huang HF (2011) Sustained endoplasmic reticulum stress as a cofactor of oxidative stress in decidual cells from patients with early pregnancy loss. J Clin Endocrinol Metab 96:E493–E497 Liu XM, Ding GL, Jiang Y, Pan HJ, Zhang D, Wang TT, Zhang RJ, Shu J, Sheng JZ, Huang HF (2012) Down-regulation of S100A11, a calcium-binding protein, in human endometrium may cause reproductive failure. J Clin Endocrinol Metab 97:3672–3683 Liu Z, Yue K, Ma S, Sun X, Tan J (2003) Effects of pregnant mare serum gonadotropin (eCG) on follicle development and granulosa-cell apoptosis in the pig. Theriogenology 59:775–785 Løset M, Mundal SB, Johnson MP, Fenstad MH, Freed KA, Lian IA, Eide IP, Bjørge L, Blangero J, Moses EK, Austgulen R (2011) A transcriptional profile of the decidua in preeclampsia. Am J Obstet Gynecol 204:84.e1-27 Luo S, Mao C, Lee B, Lee AS (2006) GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development. Mol Cell Biol 26:5688– 5697
Malhotra JD, Kaufman RJ (2007) The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18:716–731 Manabe N, Goto Y, Matsuda-Minehata F, Inoue N, Maeda A, Sakamaki K, Miyano T (2004) Regulation mechanism of selective atresia in porcine follicles: regulation of granulosa cell apoptosis during atresia. J Reprod Dev 50:493 Matsuda-Minehata F, Inoue N, Goto Y, Manabe N (2006) The regulation of ovarian granulosa cell death by pro- and anti-apoptotic molecules. J Reprod Dev 52:695–670 Mei Y, Thompson MD, Cohen RA, Tong X (2013) Endoplasmic reticulum stress and related pathological processes. J Pharmacol Biomed Anal 1:1000107 Moenner M, Pluquet O, Bouchecareilh M, Chevet E (2007) Integrated endoplasmic reticulum stress responses in cancer. Cancer Res 67: 10631–10634 Murdoch WJ (1995) Programmed cell death in preovulatory ovine follicles. Biol Reprod 53:8–12 Nakatsukasa K, Kamura T, Brodsky JL (2014) Recent technical developments in the study of ER-associated degradation. Curr Opin Cell Biol 29:82–91 Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26:9220–9231 Oh J, Riek AE, Weng S, Petty M, Kim D, Colonna M, Cella M, BernalMizrachi C (2012) Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation. J Biol Chem 287: 11629–11641 Park HJ, Park SJ, Koo DB, Kong IK, Kim MK, Kim JM, Choi MS, Park YH, Kim SU, Chang KT, Park CK, Chae JI, Lee DS (2013) Unfolding protein response signaling is involved in development, maintenance, and regression of the corpus luteum during the bovine estrous cycle. Biochem Biophys Res Commun 441:344–350 Park HJ, Park SJ, Koo DB, Lee SR, Kong IK, Ryoo JW, Park YI, Chang KT, Lee DS (2014) Progesterone production is affected by unfolded protein response (UPR) signaling during the luteal phase in mice. Life Sci 113:60–67 Park SW, Zhou Y, Lee J, Lee J, Ozcan U (2010) Sarco(endo)plasmic reticulum Ca2+−ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity. Proc Natl Acad Sci U S A 107:19320–19325 Quirk SM, Harman RM, Huber SC, Cowan RG (2000) Responsiveness of mouse corpora luteal cells to Fas antigen (CD95)-mediated apoptosis. Biol Reprod 63:49–56 Rajakoski E (1960) The ovarian follicular system in sexually mature heifers with special reference to seasonal, cyclical, and left-right variations. Acta Endocrinol Suppl (Copenh) 15:836–838 Reid RJ, Heald PJ (1970) Uptake of (3H) leucine into proteins of rat uterus during early pregnancy. Biochim Biophys Acta 204:278–279 Rueda BR, Wegner JA, Marion SL, Wahlen DD, Hoyer PB (1995) Internucleosomal DNA fragmentation in ovine luteal tissue associated with luteolysis: in vivo and in vitro analyses. Biol Reprod 52: 305–312 Rueda BR, Tilly KI, Botros IW, Jolly PD, Hansen TR, Hoyer PB, Tilly JL (1997) Increased bax and interleukin-1beta-converting enzyme messenger ribonucleic acid levels coincide with apoptosis in the bovine corpus luteum during structural regression. Biol Reprod 56:186–193 Salminen A, Kauppinen A, Suuronen T, Kaarniranta K, Ojala J (2009) ER stress in Alzheimer’s disease: a novel neuronal trigger for inflammation and Alzheimer’s pathology. J Neuroinflammation 6:41 Samali A, FitzGerald U, Deegan S, Gupta S (2010) Methods for monitoring endoplasmic reticulum stress and the unfolded protein response. Int J Cell Biol 2010:8303074 Sheveleva EV, Landowski TH, Samulitis BK, Bartholomeusz G, Powis G, Dorr RT (2012) Imexon induces an oxidative endoplasmic
Cell Tissue Res reticulum stress response in pancreatic cancer cells. Mol Cancer Res 210:392–400 Shikone T, Yamoto M, Kokawa K, Yamashita K, Nishimori K, Nakano R (1996) Apoptosis of human corpora lutea during cyclic luteal regression and early pregnancy. J Clin Endocrinol Metab 81:2376–2380 Shimada Y, Kobayashi H, Kawagoe S, Aoki K, Kaneshiro E, Shimizu H, Eto Y, Ida H, Ohashi T (2011) Endoplasmic reticulum stress induces autophagy through activation of p38 MAPK in fibroblasts from Pompe disease patients carrying c. 546G>T mutation. Mol Genet Metab 104:566–573 Siman R, Flood DG, Thinakaran G, Neumar RW (2001) Endoplasmic reticulum stress induced cysteine protease activation in cortical neurons: effect of an Alzheimer’s disease-linked presenilin-1 knock-in mutation. J Biol Chem 276:44736–44743 Simmons D, Kennedy T (2000) Induction of glucose-regulated protein 78 in rat uterine glandular epithelium during uterine sensitization for the decidual cell reaction. Biol Reprod 62:1168–1176 Simon-Szabó L, Kokas M, Mandl J, Kéri G, Csala M (2014) Metformin attenuates palmitate-induced endoplasmic reticulum stress, serine phosphorylation of IRS-1 and apoptosis in rat insulinoma cells. PLoS One 9:e9786816 Stocco C, Telleria C, Gibori G (2007) The molecular control of corpus luteum formation, function, and regression. Endocr Rev 28:117–149 Stouffer RL (2004) The function and regulation of cell populations comprising the corpus luteum during the ovarian cycle. In: Leung PCK, Adashi EY (eds) The ovary. Elseiver/Academic Press, San Diego, pp 169–184 Sugimoto M, Manabe N, Kimura Y, Myoumot A, Imai Y, Ohno H, Miyamoto H (1998) Ultrastructural changes in granulosa cells in porcine antral follicles undergoing atresia indicate apoptotic cell death. J Reprod Dev 144:7–14 Szegezdi E, Logue SE, Gorman AM, Samali A (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7: 880–885 Telleria CM, Goyeneche AA, Cavicchia JC, Stati AO, Deis RP (2001) Apoptosis induced by antigestagen RU486 in rat corpus luteum of pregnancy. Endocrine 15:147–155 Terada N, Yamamoto R, Takada T, Miyake T, Terakawa N, Wakimoto H, Taniguchi H, Li W, Kitamura Y, Matsumoto K (1989) Inhibitory effect of progesterone on cell death of mouse uterine epithelium. J Steroid Biochem 33:1091–1096 Tersey SA, Nishiki Y, Templin AT, Cabrera SM, Stull ND, Colvin SC (2012) Islet β-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model. Diabetes 61:818–827 Tirasophon W, Welihinda AA, Kaufman RJ (1998) A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev 12:1812–1824 Todd DJ, Lee A-H, Glimcher LH (2008) The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol 8:663–674 Tomita T (1960) One-side cross sterility between inbred strains of mice. Jpn J Genet 35:291 Tong XM, Lin XN, Song T, Liu L, Zhang SY (2010) Calcium-binding protein S100P is highly expressed during the implantation window in human endometrium. Fertil Steril 94:1510–1518 Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664 Wakasugi N (1973) Studies on fertility of DDK mice: reciprocal crosses between DDK and C57BL/6J strains and experimental transplantation of the ovary. J Reprod Fertil 33:283–291 Wakasugi N (1974) A genetically determined incompatibility system between spermatozoa and eggs leading to embryonic death in mice. J Reprod Fertil 41:85–96
Wang H, Dey SK (2006) Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet 7:185–199 Wang Z, Wang H, Xu ZM, Ji YL, Chen YH, Zhang ZH, Zhang C, Meng XH, Zhao M, Xu DX (2012) Cadmium-induced teratogenicity: association with ROS-mediated endoplasmic reticulum stress in placenta. Toxicol Appl Pharmacol 259:236–247 Wang Z, Jiang C, Chen W, Zhang G, Luo D, Cao Y, Wu J, Ding Y, Liu B (2014) Baicalein induces apoptosis and autophagy via endoplasmic reticulum stress in hepatocellular carcinoma cells. Biomed Res Int 2014:732516 Watson ED, Cross JC (2005) Development of structures and transport functions in the mouse placenta. Physiology (Bethesda) 20:180–193 Wu LL, Dunning KR, Yang X, Russell DL, Lane M, Norman RJ, Robker RL (2010) High-fat diet causes lipotoxicity responses in cumulusoocyte complexes and decreased fertilization rates. Endocrinology 151:5438–5445 Xu C, Bailly-Maitre B, Reed JC (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115:2656–2664 Yang ES, Bae JY, Kim TH, Kim YS, Suk K, Bae YC (2014) Involvement of endoplasmic reticulum stress response in orofacial inflammatory pain. Exp Neurobiol 23:372–380 Yang X, Wu LL, Chura LR, Liang X, Lane M, Norman RJ, Robker RL (2012) Exposure to lipid-rich follicular fluid is associated with endoplasmic reticulum stress and impaired oocyte maturation in cumulus-oocyte complexes. Fertil Steril 97:1438–1443 Yang Y, Lin P, Chen F, Wang A, Lan X, Song Y, Jin Y (2013a) Luman recruiting factor regulates endoplasmic reticulum stress in mouse ovarian granulosa cell apoptosis. Theriogenology 79:633–639 Yang Y, Jin Y, Martyn AC, Lin P, Song Y, Chen F, Hu L, Cui C, Li X, Li Q, Lu R, Wang A (2013b) Expression pattern implicates a potential role for luman recruitment factor in the process of implantation in uteri and development of preimplantation embryos in mice. J Reprod Dev 59:245–251 Yang Y, Sun M, Shan Y, Zheng X, Ma H, Ma W, Wang Z, Pei X, Wang Y (2014) Endoplasmic reticulum stress-mediated apoptotic pathway is involved in corpus luteum regression in rats. Reprod Sci 2014:pii, 1933719114553445 Yorimitsu T, Klionsky DJ (2007) Eating the endoplasmic reticulum: quality control by autophagy. Trends Cell Biol 17:279–285 Yung HW, Calabrese S, Hynx D, Hemmings BA, Cetin I, CharnockJones DS, Burton G (2008) Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction. Am J Pathol 173:451–462 Zhang D, Ma C, Sun X, Xia H, Zhang W (2012) S100P expression in response to sex steroids during the implantation window in human endometrium. Reprod Biol Endocrinol 10:106 Zhang H, Wu F, Kong X, Yang J, Chen H, Deng L, Cheng Y, Ye L, Zhu S, Zhang X, Wang Z, Shi H, Fu X, Li X, Xu H, Lin L, Xiao J (2014) Nerve growth factor improves functional recovery by inhibiting endoplasmic reticulum stress-induced neuronal apoptosis in rats with spinal cord injury. J Transl Med 12:130 Zhang J, Zhu G, Wang X, Xu B, Hu L (2007) Apoptosis and expression of protein TRAIL in granulosa cells of rats with polycystic ovarian syndrome. J Huazhong Univ Sci Technolog Med Sci 27:311–314 Zhang JY, Diao YF, Kim HR, Jin DI (2012) Inhibition of endoplasmic reticulum stress improves mouse embryo development. PLoS One 7:e40433 Zheng YZ, Cao ZG, Hu X, Shao ZM (2014) The endoplasmic reticulum stress markers GRP78 and CHOP predict disease-free survival and responsiveness to chemotherapy in breast cancer. Breast Cancer Res Treat 145:349–358 Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL, Ron D (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12:982–995
