Structural and functional diversity of the platelet-derived growth factor Thomas F. Deuel W a s h i n g t o n University School of Medicine and The Jewish Hospital, St. Louis, Missouri, USA. The platelet derived growth factor is the most potent mitogen for cells of mesenchymal origin. Recent investigations have identified and characterized the structures and genes of the isoforms of PDGF, of the isoforms of its receptor, and of genes activated by it. It is now possible to understand in part the striking diversity of activities mediated by platelet derived growth factor and to identify new roles for it in normal and abnormal cell growth, in inflammation and repair, and in mammalian development. Current Opinion in Biotechnology 1991, 2:802-806
Introduction Platelet-derived growth factor (PDGF) is a heterodimeric polypeptide of disulfide linked A- and B-chains. It is normally stored within an intracellular compartment, the platelet ey-granule,and is released to the extraceUular matrix at platelet activation sites; it interacts with target cells locally as an apparent signaling molecule for inflammation and repair [1]. Recent work from many laboratories has greatly expanded understanding of both the in vitro and in vivo properties of PDGF and the structure and regulation of the genes that encode it. As a result, important advances have been made in dissecting the mechanisms by which growth factors may act and important clues have been uncovered to identify the diverse functions mediated by polypeptide growth factors. In this article, differences in the mechanisms by which the A- and B-chains of PDGF interact with their cognate receptors in cells that express the PDGF genes will be reviewed. These differences in mechanisms may underlie the failure of the PDGF A-chain gene to transform cells whereas the PDGF B-chain gene readily transforms target cells. The role of PDGF in activating a family of new genes that encode cytokines important in inflammation and repair will also be reviewed. Finally, very recent results that suggest that PDGF may be important in development will be discussed. These divergent functional properties of PDGF suggest that PDGF and other growth factors are extraordinarily diverse in their mechanisms of action and in the signals they initiate in target cells. These properties also suggest the biological importance and therapeutic potential of this class of signaling molecules.
Background The structure of PDGF was first identified by partial amino acid sequence analyses. This led to the discov-
ery that the B-chain of PDGF is 92% homologous with sequences within the protein product of the v-s~ oncogene, p28~ ~ [2]. It was subsequently established that the c-sis gene encodes the precursor of the B-chain of PDGF and is the normal cellular counterpart of the transforming gene of the simian sarcoma virus (SSV), v-s~ [3,4]. Lysates of SSV-transformed NIH 31"3cells contain a PDGF-Iike activity that is not present in non-transformed NIH 3T3 cells [5,6]. High levels of expression of the c-st~gene have been found in cells transformed by other oncogenes and in cell lines obtained from spontaneously occurring human tumors [7,8]. These and other results have established that the PDGF B-chain is functionallyimportant in both normal and transformed cell growth. The human c-s/s gene extends over 12 kb in length, contains five exons and four introns, and encodes a transcript of 4.2 kb [7,8,9] and has been mapped to the long arm of chromosome 22. The structure of the PDGF A-chain was deduced from cDNA clones from human osteosarcoma and endothelial cell cDNA libraries [11,12]; the A-chain gene encodes transcripts of approximately 2.0, 2.2 and 2.8kb that arise from a single initiation start site [13"] and a precursor polypeptide that is approximately 50% homologous to the PDGF B-chain. In contrast to the PDGF B-chain gene, the A-chain gene is incapable of transforming NIH 3T3 cells. The homodimeric B-chain of PDGF is poorly secreted whereas PDGF A-chain homodimers are readily secreted; thus, the PDGF A-chain acts on the secreting or neighboring cells by autocrine or paracrine mechanisms [14,15]. Two structurally related PDGF receptors (eY and [3) have been identified and cloned [16-18]. Each receptor is characterized by five extracellular inununoglobulin-like domains, a single transmembrane domain, and a split tyrosine kinase domain. The two types of receptors have significant differences in ligand recognition; the ~ receptor of PDGF binds all three isoforms of PDGF (AA, AB,
Abbreviations PDGF~platelet derived growth factor; PI--phosphatidylinositol; SiC--small inducible genes; SSV--simian sarcoma virus, 802
(~) Current Biology Ltd ISSN 0958-1669
Structural and functional diversity of the platelet-deHved growth factor Deuel 803 BB) whereas the 13 receptor binds only PDGF B-chain homodimers with high affinity [19,20]. The expression of the cx and the 13receptors, like that of the PDGF iso. forms, is regulated independently [21o]. The isoforms of PDGF, and perhaps of each type of PDGF receptor, are expressed in different tissues and at different stages of development. The striking diversity of PDGF function is thus dependent upon the isomeric composition of FDGF, the independent regulation of the expression of its isomeric composition of PDGF, the independent regulation of the expression of its isomeric homodimers and receptors and different multiple activities that each isoform may mediate in conjunction with the two receptor types as expressed in specific cell-types. Its diversity is also dependent upon the developmental stage-specific expression of the PDGF genes and the PDGF receptor genes. The PDGF isoforms do not circulate and are thus distinct from hormones. Therefore, the influence of PDGF is limited to the immediate environment of the cell that expresses the PDGF genes and of the cells expressing its receptors. This localized influence of the PDGF growth factor family permits striking diversity of activities in development and in unrelated tissues.
PDGF B-chain activates cells during processing According to the autocrine hypothesis [15], unregulated growth of transformed cells may occur through the secretion of growth factors and their subsequent productive interaction with cell-surface receptors of the secreting cells. The autocrine hypothesis, however, is inadequate to fully explain the mechanism by which SSV induces transformation. High concentrations of antisera to PDGF in media of SSV.transformed cells do not reverse the transformed phenotype, and high levels of exogenous p28v-~ in continuous cultures of nontransformed cells do not induce morphological transformation [22]. Thus, secretion of v-sis into media is not required for transformation by v-s/x An internal autoactivation mechanism has been proposed for transformation by v-s/s (and by the PDGF B-chain) as an alternative model [14,22,23]. It was proposed that the Interaction of v-s~ product with its receptor is compartmentaliTed within the endoplasmic reticulum/Golgi complex as both growth factor and receptor are processed in the secretory pathway. Evidence in support of this mechanism has been obtained. First, limited tyrosine phosphorytation of the PDGF [3 receptor during its processing has been observed In SSV-transformed NIH 3T3 and NRK cells [24,25], and, both the receptor and the v-s~ product may undergo internal degradation in v-s/~tmnsformed cells [26]. Second, if the v-st~ gene product is retained in the endoplasmic reticulum, as a result of engineering the v-s/s gene so that its product contains the endoplasmic retention signal KDEL [27] in its carboxyt terminus, v-st~ 15 fully transforming
[221. More recently it has been shown that transformation by v-st~correlates directtywith the rapid internal degradation of the precursor forms of both the cc and the 13 PDGF receptors, with the failure of either of these receptors
to be fully processed, and with the association of high levels of phosphatidylinositol (FI)-3 kinase activity with immunoprecipitates of the PI-3 kinase signalling pathway contrasts strikingly with the failure of the FDGF receptor [23]. PI-3 kinase associates only with the activated PDGF receptors. The ability of the v-sB gene product to autoacfivate the FDGF receptors within the processing compartments and to initiate activation of the PI-3 kinase signalling pathway contrasts strikingly" with the failureof the PDGF A-chain to activate its receptor intracellulady, and to induce transformation when endogenously expressed at high levels. These results suggest that cells will be transformed if they express both the PDGF B-chain and its receptors; paracrine regulation by endogenously expressed PDGF-B is not necessary. The results also suggest that the internal autoactivation of PDGF receptors may be essential for transformation by v-s/~ and that the failure of the PDGF A-chain to transform cells may be related to its failure to activate its receptor internally.
PDGF as a model cytokine in inflammation and wound healing In addition to being a potent mitogen, PDGF acts as a chemotactic factor [28-30]. It also activates neutrophils, monocytes, and fibroblasts [31,32]. These different functions are essential to the processes of inflammation and wound healing. FDGF also induces new gene expression which, when fully understood, may also contribute greatly to elucidating the diverse functions of PDGF. These otherwise quiescent genes that are induced early in response to PDGF include genes that mediate the intraceIIular propagation of the mitogenic signal, such as c-fos and c-myc [33-35]. PDGF also induces the early expression of genes that encode cytokines that may be important for intercellular communication. Thus, the JE and KC genes induced by PDGF [36-38] and other related genes encode proteins that are themselves regulators of inflammatory/immune regulatory cells and which appear to coordinate additional responses associated with wounds, infection, and healing.
JE and KC were first identified by differential hybridization [33,34] and have recently been shown to belong to a superfamily of small inducible genes (SIG) [35]. This family also indudes the platelet ct granule proteins, platelet factor-4 and ~-thromboglobulin. The murine JE gene is composed of three exons and two introns and encodes a 148 amino-acid basic polypeptide [34,35]; both rat and murine JE gene products contain amino-terminal hydrophobic leader sequences. A human homolog of the mouse JE gene has been identified that is approximately 68% identical to the monocyte chemotactic protein-1 [39], which appears to be identical to a recently described smooth muscle cell chemotactic factor [40-43]. The JEgene and other members of this newly recognized SIG family are induced by cytokines which are associated with inflammation, repair, or the immune response. Two subgroups of the SIG family have been identified based upon a Cys-Cys motif or a Cys-X-Cys motif (where X is any amino acid). These subgroups
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Mammalian gene studies
may represent tandem duplications of related SIG family members [44,45], all of which appear to have evolved from a common ancestor. These results appear to support the view that the PDGF family o f growth factors act in part through the initiation of new gene expression that may release other cytokine signals active in inflammation and repair in a highly regulated fashion. J/~ a potent monocyte chemo-attractant, may be a protype of this PDGF-inducible gene family product. The results described above coupled with the potency of PDGF for attracting inflammatory cells chemotactically have prompted the use of PDGF as a wound healing agent in experimental animals. Thus, PDGF has been added directly to linear incisional wounds in the rat [46] and to a dermal ulcer model in the rabbit ear [47"]. PDGF has enhanced the strength required to disrupt wounds, in direct correlation with new collagen synthesis, over the first ten weeks after wounding in the linear incisions. PDGF also increased the rate of epithelialization, granulation tissue formation and neovascular~tion of wounds in rabbits. Inflammatory ceU migration and fibroblast influx into these wounds is enhanced by PDGF and the collagen content is increased. These experiments in vivo directly support the importance of PDGF in wound healing.
PDGF as a developmental signal The potency of PDGF as a rnitogen and chemo-attractant for diverse cell types suggests that the PDGF family may function in development. Striking evidence in support of this suggestion has been obtained by the strong in situ hybridiT~tion signal of a cRNA probe o f the PDGF A-chain gene within neurons in peripheral and central nervous systems of embryonic and adult mice [48-]. The transcripts of the PDGF A-chain gene were observed in most ff not all neurons late in embryogenesis, between 12-15 days, and also at high levels in mature mouse brain and spinal cord [48.]. The expression of the PDGF Achain gene is developmentally regulated and tissue specific, but PDGF is ubiquitously expressed in neurons in contrast to other known neurotrophic molecules that show more restricted expression [49,50]. The highly regulated spatial and developmental expression of PDGF A-chain strongly suggests a role for PDGF in development. The secretion of PDGF A-chain products at much higher levels that B-chain products, and its potency both as a chemo-attractrant and as a mitogen, are properties that are also ideally suited to a developmental role for PDGF-A in the central nervous system. In recent work, it has been shown that the gene for the PDGF et receptor is expressed in glial cells but not in neurons (H-J Yeh, unpublished data), thus further supporting the possible function of the PDGF A-chain in the development of the central nervous system, and suggesting that it may attract and interact with gLial cells that express the PDGF ct receptor. Expression of the PDGF et receptor occurs before the differentiation of most types of glial cells and before the major migration of glial cells in the central nervous system. In vitro evidence also supports a potential role o f PDGF in development. The sequential differentiation of the so-
called O-2A progenitor cells into oligodendrocytes and type 2 astrocytes in vitro appears to depend upon the stimulation of O-2A progenitor cells by PDGF [51]. I n vivo, oligodendrocytes appear over a period o f weeks, beginning at parturition [52]. The timing of oligodendrocyte development can be reconstituted in vitro if PDGF is added to the culture medium [53,54]. PDGF is also mitogenic for O-2A progenitor cells in vitro [53], further supporting in vivo roles of PDGF as a regulatory factor in the differentiation o f ollgodendrocytes. The PDGF B-chain has also been observed in neurons o f the central nervous system [55"]. PDGF [3 receptors have been described in rat brain neurons, and the treatment o f neuron-enriched cultures with PDGF B-chain resulted in outgrowth of neurites and prolonged survival [56]. Thus, the [3-chain of PDGF may also be an important developmental regulator in the central nervous system, although detailed experiments are needed to determine the precise temporal expression of both the PDGF B-chain and the PDGF [3-receptor genes.
Conclusions The field of PDGF research has rapidly expanded with the increased characterization o f PDGF, its receptors, and the PDGF inducible genes. It had previously been recognized that the regulation of PDGF is important in normal and transformed cells. It is n o w clear that the spectrum of the relative alfinities of the PDGF isomers and their interactions with the PDGF receptors also provides for an extraordinary diversity o f responses. These interactions may well be important in determining the particular cellular and molecular activities of PDGF at sites where cells express and release PDGF. More detailed studies o f the structure and function o f the PDGF genes, the PDGF receptor genes, and the PDGF-induced genes should provide new insight into the role of PDGF in development and tumorgenesis.
Acknowledgements This work was supported by National Institutes of Health grants HL31102, HL14147,CA49712, and a grant from the Monsanto Corporation.
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TF Deuel, Departments of Medicine and Biochemistry and Molecular Biophysics, Washinston University School of Medicine and Jewish Hospital, St Louis, Missouri 63110, USA.
47. •
Introduction Platelet-derived growth factor (PDGF) is a heterodimeric polypeptide of disulfide linked A- and B-chains. It is normally stored within an intracellular compartment, the platelet ey-granule,and is released to the extraceUular matrix at platelet activation sites; it interacts with target cells locally as an apparent signaling molecule for inflammation and repair [1]. Recent work from many laboratories has greatly expanded understanding of both the in vitro and in vivo properties of PDGF and the structure and regulation of the genes that encode it. As a result, important advances have been made in dissecting the mechanisms by which growth factors may act and important clues have been uncovered to identify the diverse functions mediated by polypeptide growth factors. In this article, differences in the mechanisms by which the A- and B-chains of PDGF interact with their cognate receptors in cells that express the PDGF genes will be reviewed. These differences in mechanisms may underlie the failure of the PDGF A-chain gene to transform cells whereas the PDGF B-chain gene readily transforms target cells. The role of PDGF in activating a family of new genes that encode cytokines important in inflammation and repair will also be reviewed. Finally, very recent results that suggest that PDGF may be important in development will be discussed. These divergent functional properties of PDGF suggest that PDGF and other growth factors are extraordinarily diverse in their mechanisms of action and in the signals they initiate in target cells. These properties also suggest the biological importance and therapeutic potential of this class of signaling molecules.
Background The structure of PDGF was first identified by partial amino acid sequence analyses. This led to the discov-
ery that the B-chain of PDGF is 92% homologous with sequences within the protein product of the v-s~ oncogene, p28~ ~ [2]. It was subsequently established that the c-sis gene encodes the precursor of the B-chain of PDGF and is the normal cellular counterpart of the transforming gene of the simian sarcoma virus (SSV), v-s~ [3,4]. Lysates of SSV-transformed NIH 31"3cells contain a PDGF-Iike activity that is not present in non-transformed NIH 3T3 cells [5,6]. High levels of expression of the c-st~gene have been found in cells transformed by other oncogenes and in cell lines obtained from spontaneously occurring human tumors [7,8]. These and other results have established that the PDGF B-chain is functionallyimportant in both normal and transformed cell growth. The human c-s/s gene extends over 12 kb in length, contains five exons and four introns, and encodes a transcript of 4.2 kb [7,8,9] and has been mapped to the long arm of chromosome 22. The structure of the PDGF A-chain was deduced from cDNA clones from human osteosarcoma and endothelial cell cDNA libraries [11,12]; the A-chain gene encodes transcripts of approximately 2.0, 2.2 and 2.8kb that arise from a single initiation start site [13"] and a precursor polypeptide that is approximately 50% homologous to the PDGF B-chain. In contrast to the PDGF B-chain gene, the A-chain gene is incapable of transforming NIH 3T3 cells. The homodimeric B-chain of PDGF is poorly secreted whereas PDGF A-chain homodimers are readily secreted; thus, the PDGF A-chain acts on the secreting or neighboring cells by autocrine or paracrine mechanisms [14,15]. Two structurally related PDGF receptors (eY and [3) have been identified and cloned [16-18]. Each receptor is characterized by five extracellular inununoglobulin-like domains, a single transmembrane domain, and a split tyrosine kinase domain. The two types of receptors have significant differences in ligand recognition; the ~ receptor of PDGF binds all three isoforms of PDGF (AA, AB,
Abbreviations PDGF~platelet derived growth factor; PI--phosphatidylinositol; SiC--small inducible genes; SSV--simian sarcoma virus, 802
(~) Current Biology Ltd ISSN 0958-1669
Structural and functional diversity of the platelet-deHved growth factor Deuel 803 BB) whereas the 13 receptor binds only PDGF B-chain homodimers with high affinity [19,20]. The expression of the cx and the 13receptors, like that of the PDGF iso. forms, is regulated independently [21o]. The isoforms of PDGF, and perhaps of each type of PDGF receptor, are expressed in different tissues and at different stages of development. The striking diversity of PDGF function is thus dependent upon the isomeric composition of FDGF, the independent regulation of the expression of its isomeric composition of PDGF, the independent regulation of the expression of its isomeric homodimers and receptors and different multiple activities that each isoform may mediate in conjunction with the two receptor types as expressed in specific cell-types. Its diversity is also dependent upon the developmental stage-specific expression of the PDGF genes and the PDGF receptor genes. The PDGF isoforms do not circulate and are thus distinct from hormones. Therefore, the influence of PDGF is limited to the immediate environment of the cell that expresses the PDGF genes and of the cells expressing its receptors. This localized influence of the PDGF growth factor family permits striking diversity of activities in development and in unrelated tissues.
PDGF B-chain activates cells during processing According to the autocrine hypothesis [15], unregulated growth of transformed cells may occur through the secretion of growth factors and their subsequent productive interaction with cell-surface receptors of the secreting cells. The autocrine hypothesis, however, is inadequate to fully explain the mechanism by which SSV induces transformation. High concentrations of antisera to PDGF in media of SSV.transformed cells do not reverse the transformed phenotype, and high levels of exogenous p28v-~ in continuous cultures of nontransformed cells do not induce morphological transformation [22]. Thus, secretion of v-sis into media is not required for transformation by v-s/x An internal autoactivation mechanism has been proposed for transformation by v-s/s (and by the PDGF B-chain) as an alternative model [14,22,23]. It was proposed that the Interaction of v-s~ product with its receptor is compartmentaliTed within the endoplasmic reticulum/Golgi complex as both growth factor and receptor are processed in the secretory pathway. Evidence in support of this mechanism has been obtained. First, limited tyrosine phosphorytation of the PDGF [3 receptor during its processing has been observed In SSV-transformed NIH 3T3 and NRK cells [24,25], and, both the receptor and the v-s~ product may undergo internal degradation in v-s/~tmnsformed cells [26]. Second, if the v-st~ gene product is retained in the endoplasmic reticulum, as a result of engineering the v-s/s gene so that its product contains the endoplasmic retention signal KDEL [27] in its carboxyt terminus, v-st~ 15 fully transforming
[221. More recently it has been shown that transformation by v-st~correlates directtywith the rapid internal degradation of the precursor forms of both the cc and the 13 PDGF receptors, with the failure of either of these receptors
to be fully processed, and with the association of high levels of phosphatidylinositol (FI)-3 kinase activity with immunoprecipitates of the PI-3 kinase signalling pathway contrasts strikingly with the failure of the FDGF receptor [23]. PI-3 kinase associates only with the activated PDGF receptors. The ability of the v-sB gene product to autoacfivate the FDGF receptors within the processing compartments and to initiate activation of the PI-3 kinase signalling pathway contrasts strikingly" with the failureof the PDGF A-chain to activate its receptor intracellulady, and to induce transformation when endogenously expressed at high levels. These results suggest that cells will be transformed if they express both the PDGF B-chain and its receptors; paracrine regulation by endogenously expressed PDGF-B is not necessary. The results also suggest that the internal autoactivation of PDGF receptors may be essential for transformation by v-s/~ and that the failure of the PDGF A-chain to transform cells may be related to its failure to activate its receptor internally.
PDGF as a model cytokine in inflammation and wound healing In addition to being a potent mitogen, PDGF acts as a chemotactic factor [28-30]. It also activates neutrophils, monocytes, and fibroblasts [31,32]. These different functions are essential to the processes of inflammation and wound healing. FDGF also induces new gene expression which, when fully understood, may also contribute greatly to elucidating the diverse functions of PDGF. These otherwise quiescent genes that are induced early in response to PDGF include genes that mediate the intraceIIular propagation of the mitogenic signal, such as c-fos and c-myc [33-35]. PDGF also induces the early expression of genes that encode cytokines that may be important for intercellular communication. Thus, the JE and KC genes induced by PDGF [36-38] and other related genes encode proteins that are themselves regulators of inflammatory/immune regulatory cells and which appear to coordinate additional responses associated with wounds, infection, and healing.
JE and KC were first identified by differential hybridization [33,34] and have recently been shown to belong to a superfamily of small inducible genes (SIG) [35]. This family also indudes the platelet ct granule proteins, platelet factor-4 and ~-thromboglobulin. The murine JE gene is composed of three exons and two introns and encodes a 148 amino-acid basic polypeptide [34,35]; both rat and murine JE gene products contain amino-terminal hydrophobic leader sequences. A human homolog of the mouse JE gene has been identified that is approximately 68% identical to the monocyte chemotactic protein-1 [39], which appears to be identical to a recently described smooth muscle cell chemotactic factor [40-43]. The JEgene and other members of this newly recognized SIG family are induced by cytokines which are associated with inflammation, repair, or the immune response. Two subgroups of the SIG family have been identified based upon a Cys-Cys motif or a Cys-X-Cys motif (where X is any amino acid). These subgroups
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may represent tandem duplications of related SIG family members [44,45], all of which appear to have evolved from a common ancestor. These results appear to support the view that the PDGF family o f growth factors act in part through the initiation of new gene expression that may release other cytokine signals active in inflammation and repair in a highly regulated fashion. J/~ a potent monocyte chemo-attractant, may be a protype of this PDGF-inducible gene family product. The results described above coupled with the potency of PDGF for attracting inflammatory cells chemotactically have prompted the use of PDGF as a wound healing agent in experimental animals. Thus, PDGF has been added directly to linear incisional wounds in the rat [46] and to a dermal ulcer model in the rabbit ear [47"]. PDGF has enhanced the strength required to disrupt wounds, in direct correlation with new collagen synthesis, over the first ten weeks after wounding in the linear incisions. PDGF also increased the rate of epithelialization, granulation tissue formation and neovascular~tion of wounds in rabbits. Inflammatory ceU migration and fibroblast influx into these wounds is enhanced by PDGF and the collagen content is increased. These experiments in vivo directly support the importance of PDGF in wound healing.
PDGF as a developmental signal The potency of PDGF as a rnitogen and chemo-attractant for diverse cell types suggests that the PDGF family may function in development. Striking evidence in support of this suggestion has been obtained by the strong in situ hybridiT~tion signal of a cRNA probe o f the PDGF A-chain gene within neurons in peripheral and central nervous systems of embryonic and adult mice [48-]. The transcripts of the PDGF A-chain gene were observed in most ff not all neurons late in embryogenesis, between 12-15 days, and also at high levels in mature mouse brain and spinal cord [48.]. The expression of the PDGF Achain gene is developmentally regulated and tissue specific, but PDGF is ubiquitously expressed in neurons in contrast to other known neurotrophic molecules that show more restricted expression [49,50]. The highly regulated spatial and developmental expression of PDGF A-chain strongly suggests a role for PDGF in development. The secretion of PDGF A-chain products at much higher levels that B-chain products, and its potency both as a chemo-attractrant and as a mitogen, are properties that are also ideally suited to a developmental role for PDGF-A in the central nervous system. In recent work, it has been shown that the gene for the PDGF et receptor is expressed in glial cells but not in neurons (H-J Yeh, unpublished data), thus further supporting the possible function of the PDGF A-chain in the development of the central nervous system, and suggesting that it may attract and interact with gLial cells that express the PDGF ct receptor. Expression of the PDGF et receptor occurs before the differentiation of most types of glial cells and before the major migration of glial cells in the central nervous system. In vitro evidence also supports a potential role o f PDGF in development. The sequential differentiation of the so-
called O-2A progenitor cells into oligodendrocytes and type 2 astrocytes in vitro appears to depend upon the stimulation of O-2A progenitor cells by PDGF [51]. I n vivo, oligodendrocytes appear over a period o f weeks, beginning at parturition [52]. The timing of oligodendrocyte development can be reconstituted in vitro if PDGF is added to the culture medium [53,54]. PDGF is also mitogenic for O-2A progenitor cells in vitro [53], further supporting in vivo roles of PDGF as a regulatory factor in the differentiation o f ollgodendrocytes. The PDGF B-chain has also been observed in neurons o f the central nervous system [55"]. PDGF [3 receptors have been described in rat brain neurons, and the treatment o f neuron-enriched cultures with PDGF B-chain resulted in outgrowth of neurites and prolonged survival [56]. Thus, the [3-chain of PDGF may also be an important developmental regulator in the central nervous system, although detailed experiments are needed to determine the precise temporal expression of both the PDGF B-chain and the PDGF [3-receptor genes.
Conclusions The field of PDGF research has rapidly expanded with the increased characterization o f PDGF, its receptors, and the PDGF inducible genes. It had previously been recognized that the regulation of PDGF is important in normal and transformed cells. It is n o w clear that the spectrum of the relative alfinities of the PDGF isomers and their interactions with the PDGF receptors also provides for an extraordinary diversity o f responses. These interactions may well be important in determining the particular cellular and molecular activities of PDGF at sites where cells express and release PDGF. More detailed studies o f the structure and function o f the PDGF genes, the PDGF receptor genes, and the PDGF-induced genes should provide new insight into the role of PDGF in development and tumorgenesis.
Acknowledgements This work was supported by National Institutes of Health grants HL31102, HL14147,CA49712, and a grant from the Monsanto Corporation.
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TF Deuel, Departments of Medicine and Biochemistry and Molecular Biophysics, Washinston University School of Medicine and Jewish Hospital, St Louis, Missouri 63110, USA.
47. •
