Clin Genet 2014: 86: 453–460 Printed in Singapore. All rights reserved
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12493
Developmental Biology: Frontiers for Clinical Genetics Section Editors: Jacques L. Michaud, e-mail: [email protected] Bruno Reversade, e-mail: [email protected]
Genetic regulation of vertebrate eye development Zagozewski J.L., Zhang Q., Eisenstat D.D. Genetic regulation of vertebrate eye development. Clin Genet 2014: 86: 453–460. © John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2014 Eye development is a complex and highly regulated process that consists of several overlapping stages: (i) specification then splitting of the eye field from the developing forebrain; (ii) genesis and patterning of the optic vesicle; (iii) regionalization of the optic cup into neural retina and retina pigment epithelium; and (iv) specification and differentiation of all seven retinal cell types that develop from a pool of retinal progenitor cells in a precise temporal and spatial manner: retinal ganglion cells, horizontal cells, cone photoreceptors, amacrine cells, bipolar cells, rod photoreceptors and Müller glia. Genetic regulation of the stages of eye development includes both extrinsic (such as morphogens, growth factors) and intrinsic factors (primarily transcription factors of the homeobox and basic helix-loop helix families). In the following review, we will provide an overview of the stages of eye development highlighting the role of several important transcription factors in both normal developmental processes and in inherited human eye diseases. Conflict of interest
None to declare.
J.L. Zagozewskia , Q. Zhangb and D.D. Eisenstata,c,d a Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada, b Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada, c Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada, and d Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
Key words: bHLH genes – eye malformations – genetic eye diseases – homeobox genes – retina development – transcription factor Corresponding author: Professor David D. Eisenstat, MD, MA, FRCPC, Departments of Pediatrics and Medical Genetics, Room 8-43B Medical Sciences Building, University of Alberta, Edmonton AB T6G 2H7, Canada. Tel.:780-492-9738; fax: 780-492-1998; e-mail: [email protected] Received 30 June 2014, revised and accepted for publication 20 August 2014
Vertebrate eye development is a complex process regulated by intrinsic and extrinsic factors that work in concert to specify an area of the forebrain as the prospective eye field (EF), and then produce the neural retina (NR). Their importance is shown in the ocular abnormalities that result from inherited mutations (Table 1). Eye development begins at the late gastrula stage when the EF is organized and bilaterally separated in the neural plate (1, 2). At embryonic day (E) 8.5, the optic vesicles (OVs) appear and evaginate laterally from the forebrain, growing towards the overlying surface
ectoderm (Fig. 1a, Table 2) (3). As the OV comes in close contact with the surface ectoderm, the surface ectoderm thickens into the lens placode (LP). Then, the OV and the LP invaginate, forming the optic cup (OC) and the lens (Fig. 1b,c). The OC consists of two layers: the retinal pigment epithelium (RPE) and the NR. The NR develops further into the mature trilaminated retina (Fig. 1d). In this review, we highlight the genetic mechanisms integral to eye development, with an emphasis on the NR and on the role of basic helix-loop-helix (bHLH) and homeobox gene transcription factors.
453
Zagozewski et al. Table 1. Transcription factors mutated in ocular diseases Transcription factor
Disease(s)
Crx
Cone-rod dystrophy Leber congenital amaurosis Retinitis pigmentosa Microphthalmia Aniridia Ocular coloboma Coloboma of optic nerve Microphthalmia Holoprosencephaly Microphthalmia with cataract Microphthalmia Micropththalmia Micropththlamia with coloboma
Nrl Otx2 Pax6
Rax Six3 Six6 Vax1 Vsx2
Phenotype MIM number
Gene MIM number
120970 613829 613750 610125 106210 120200 120430 611038 157170 212550 614402 610093 610092
602225 602225 162080 600037 607108 607108 607108 601881 603714 606326 604294 142993 142993
Fig. 1. Overview of vertebrate eye development. The OVs are the first visible structures of the vertebrate eye. The OVs evaginate from the midline of the forebrain towards the overlying SE (a). Once OV contact is made with the thickened SE, which is now the LP, invagination of the OV and the LP develop into the OC and the LV, respectively (b). The OC is divided into the NR and the RPE (c). The NR is further specified into six distinct neural cell types: RGC (purple), AC (orange), BC (green), HC (light blue), cone PR (red) and rod PR (dark blue) and one glial cell (not shown). The retina is organized into three cellular layers including the GCL, the INL and the ONL. Synaptic connections between the cellular layers are maintained in the IPL and the OPL (d). GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; LP, lens placode; LV, lens vesicle; NR, neural retina; OC, optic cup; OV, optic vesicle; SE, surface ectoderm.
Eye field specification
The eyes are an extension of the developing forebrain with EF specification preceded by neural induction and patterning. Graded Wnt signalling is required to establish anterior–posterior (A–P) polarity in the developing forebrain with increased Wnt signalling promoting posterior neural fates (4–6). Wnt mutants have reduced/absent eyes and telencephalon, while the diencephalon expands anteriorly (7).
454
In the anterior neural plate, the EF is specified by the coordinated expression of the EF transcription factors (EFTFs). EFTFs have been best studied in Xenopus laevis and include Rx1/Rax, Pax6, Six3, Lhx2, tll/Tlx, Optx2/Six6 and ET/Tbx3 (8). Loss of function of individual EFTFs, including Rax, Pax6, Six3 and Lhx2, leads to abnormal or absent eyes, showing their importance in early eye development (9–12). In humans, RAX and PAX6 mutations result in anophthalmia and aniridia,
Review of eye development Table 2. Key developmental stages in vertebrate eye development (3) Eye developmental stage
Days gestation (human)
Embryonic age (in days) (mouse)
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12493
Developmental Biology: Frontiers for Clinical Genetics Section Editors: Jacques L. Michaud, e-mail: [email protected] Bruno Reversade, e-mail: [email protected]
Genetic regulation of vertebrate eye development Zagozewski J.L., Zhang Q., Eisenstat D.D. Genetic regulation of vertebrate eye development. Clin Genet 2014: 86: 453–460. © John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2014 Eye development is a complex and highly regulated process that consists of several overlapping stages: (i) specification then splitting of the eye field from the developing forebrain; (ii) genesis and patterning of the optic vesicle; (iii) regionalization of the optic cup into neural retina and retina pigment epithelium; and (iv) specification and differentiation of all seven retinal cell types that develop from a pool of retinal progenitor cells in a precise temporal and spatial manner: retinal ganglion cells, horizontal cells, cone photoreceptors, amacrine cells, bipolar cells, rod photoreceptors and Müller glia. Genetic regulation of the stages of eye development includes both extrinsic (such as morphogens, growth factors) and intrinsic factors (primarily transcription factors of the homeobox and basic helix-loop helix families). In the following review, we will provide an overview of the stages of eye development highlighting the role of several important transcription factors in both normal developmental processes and in inherited human eye diseases. Conflict of interest
None to declare.
J.L. Zagozewskia , Q. Zhangb and D.D. Eisenstata,c,d a Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada, b Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada, c Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada, and d Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
Key words: bHLH genes – eye malformations – genetic eye diseases – homeobox genes – retina development – transcription factor Corresponding author: Professor David D. Eisenstat, MD, MA, FRCPC, Departments of Pediatrics and Medical Genetics, Room 8-43B Medical Sciences Building, University of Alberta, Edmonton AB T6G 2H7, Canada. Tel.:780-492-9738; fax: 780-492-1998; e-mail: [email protected] Received 30 June 2014, revised and accepted for publication 20 August 2014
Vertebrate eye development is a complex process regulated by intrinsic and extrinsic factors that work in concert to specify an area of the forebrain as the prospective eye field (EF), and then produce the neural retina (NR). Their importance is shown in the ocular abnormalities that result from inherited mutations (Table 1). Eye development begins at the late gastrula stage when the EF is organized and bilaterally separated in the neural plate (1, 2). At embryonic day (E) 8.5, the optic vesicles (OVs) appear and evaginate laterally from the forebrain, growing towards the overlying surface
ectoderm (Fig. 1a, Table 2) (3). As the OV comes in close contact with the surface ectoderm, the surface ectoderm thickens into the lens placode (LP). Then, the OV and the LP invaginate, forming the optic cup (OC) and the lens (Fig. 1b,c). The OC consists of two layers: the retinal pigment epithelium (RPE) and the NR. The NR develops further into the mature trilaminated retina (Fig. 1d). In this review, we highlight the genetic mechanisms integral to eye development, with an emphasis on the NR and on the role of basic helix-loop-helix (bHLH) and homeobox gene transcription factors.
453
Zagozewski et al. Table 1. Transcription factors mutated in ocular diseases Transcription factor
Disease(s)
Crx
Cone-rod dystrophy Leber congenital amaurosis Retinitis pigmentosa Microphthalmia Aniridia Ocular coloboma Coloboma of optic nerve Microphthalmia Holoprosencephaly Microphthalmia with cataract Microphthalmia Micropththalmia Micropththlamia with coloboma
Nrl Otx2 Pax6
Rax Six3 Six6 Vax1 Vsx2
Phenotype MIM number
Gene MIM number
120970 613829 613750 610125 106210 120200 120430 611038 157170 212550 614402 610093 610092
602225 602225 162080 600037 607108 607108 607108 601881 603714 606326 604294 142993 142993
Fig. 1. Overview of vertebrate eye development. The OVs are the first visible structures of the vertebrate eye. The OVs evaginate from the midline of the forebrain towards the overlying SE (a). Once OV contact is made with the thickened SE, which is now the LP, invagination of the OV and the LP develop into the OC and the LV, respectively (b). The OC is divided into the NR and the RPE (c). The NR is further specified into six distinct neural cell types: RGC (purple), AC (orange), BC (green), HC (light blue), cone PR (red) and rod PR (dark blue) and one glial cell (not shown). The retina is organized into three cellular layers including the GCL, the INL and the ONL. Synaptic connections between the cellular layers are maintained in the IPL and the OPL (d). GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; LP, lens placode; LV, lens vesicle; NR, neural retina; OC, optic cup; OV, optic vesicle; SE, surface ectoderm.
Eye field specification
The eyes are an extension of the developing forebrain with EF specification preceded by neural induction and patterning. Graded Wnt signalling is required to establish anterior–posterior (A–P) polarity in the developing forebrain with increased Wnt signalling promoting posterior neural fates (4–6). Wnt mutants have reduced/absent eyes and telencephalon, while the diencephalon expands anteriorly (7).
454
In the anterior neural plate, the EF is specified by the coordinated expression of the EF transcription factors (EFTFs). EFTFs have been best studied in Xenopus laevis and include Rx1/Rax, Pax6, Six3, Lhx2, tll/Tlx, Optx2/Six6 and ET/Tbx3 (8). Loss of function of individual EFTFs, including Rax, Pax6, Six3 and Lhx2, leads to abnormal or absent eyes, showing their importance in early eye development (9–12). In humans, RAX and PAX6 mutations result in anophthalmia and aniridia,
Review of eye development Table 2. Key developmental stages in vertebrate eye development (3) Eye developmental stage
Days gestation (human)
Embryonic age (in days) (mouse)
