The eye is a very complex structure that originates from a number of sources, the retina, posterior layer of iris and optic nerve developing from the neuroectoderm of the forebrain. The cornea epithelium and lens originate from surface ectoderm. The fibrous and vascular coats of the eye developing from the mesoderm between the neuroectoderm and surface ectoderm. The sclera, choroid and corneal endothelium originate from the neural crest cells that migrate into the mesenchyme (Moore K. 2008). During gastrulation, the eye developing with centrally located single eye field, after that it separates into two lateral optic vesicles (Graw, 2003).
Eye development can be divided into three phases. The first phase is the induction and regional specification and formation of the major structures of the eye. The second is development of the eye to become functional eye, and the third phase is neuronal connections formation between retina and the optic tectum (Jean et al., 1998).
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Development of the eye start at about 22 days' gestation (Human Carnegie stage 10) (Carlson B 2004). The lateral walls of the diencephalon begin to bulge out forming optic grooves or optic placodes, on both side of the presumptive forebrain region (Graw, 1996). The optic grooves grows forming the optic vesicles (O'Rahilly, 1983) which will project from the wall of forebrain into the adjacent mesenchyme (Moore K, 2008). It becomes close to the overlying surface ectoderm (Graw, 1996). The distal end of the optic vesicles start to grow and their connection with the forebrain will get narrow to form hollow optic stalk (Moore K, 2008).
In 28 days embryos (stage 13), the outer surface of the optic vesicles draw inward to form the optic cups (Graw, 1996). The optic fissure will develop on the ventral surface of the optic cups and along the optic stalks. Figure (1). Within the fissure, there is vascular mesenchyme from which the hyaloids vessels will develop. Figure (2) (Moore K, 2008). The hyaloid artery terminate at the posterior wall of the lens passing through the retina and vitreous body. As development progresses, The distal part of the hyaloid artery in the vitreous body will degenerate leaving a hyaloid canal. However, the proximal part persists as the central artery of the retina (Carlson B, 2004).
Formation of Lens and Cornea:
The first recognized inductive processes for the induction of the lens placodes is The contact between the optic vesicle and overlying ectoderm (Graw, 1996). The lens placodes invaginate through the surface ectoderm, forming lens pits. The edge of the pits approach each other and fuse to form rounded lens vesicles. Eventually, it will lose the connection with the surface ectoderm and entered the cavities of the optic cup (Moore K, 2008). It is almost complete at human Carnegie stage 14. Figure (1). (O'Rahilly, 1983).
The lens vesicle then becomes a new inductive response for corneal development (Carlson B 2004). The lens vesicle will interact with the overlying surface ectoderm leading to changing the typical surface ectoderm to a multilayered, transparent, avascualr cornea (Graw, 1996). The cornea is formed from tow origins, the surface ectoderm which will develop to the external corneal epithelium and the corneal endothelium originating from the neural crest cells that will migrate from the lip of the optic cup. (Moore K. 2008).
Retina, Iris, Ciliary Body and Optic Nerve:
At the same time while the lens and the cornea are developing, the two layers of the optic cup start to differentiate into inner neural retina and outer pigmented layer of the retina. Also, the outer margin of the optic cup, where the developing pigmented and neural retinas meet, will differentiate into iris and ciliary body. Figure (3). (Graw, 1996). The neural crest cells will migrate into the iris forming its stroma (Moore K, 2008). In humans, the development of the neural retina development will continue postnatally (Graw, 1996).
Around day 47 of gestation, the retinal differentiation start. Cones and rods can first be distinguished at week 15 of gestation. The development will continue until the eighth month. The fovea centralis (the point of maximum optical resolution) will become fully functional only after birth (Graw, 2003).
The optic stalk will be formed and it will connect the brain and eye. The axons within the neural retina will join at the base of the eye and pass down through the optic stalk. These axons will grow to form the optic nerve. Figure (4). The axons of the optic nerve become myelinated starting from the seventh month of gestation (Graw, 2003) but the mylination completed at 10 weeks after birth (Moore K, 2008). The optic nerve is 3 mm thick at birth, but its diameter will increase until 6-8 years after birth (Graw, 2003).
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Figure (1): Early development of the human eye. (Carlson B, 2004).
Figure ( 2 ): Optic cup and stalk showing the choroid fissure containing the hyaloid artery. (Carlson B, 2004).
Figure (3): Development of the iris and ciliary body.
Figure (4): Later stages of eye development with optic nerve seen.
Choroid and Sclera:
The mesenchymal cells of neural crest origin forming a layer outside the optic disc. They will start to differentiate into structures that provide vascular and mechanical support for the eye. This occur in response to an inductive power from the retinal pigmented epithelium. The innermost cells will form the choroid, a highly vascular layer. The densely collagenous, white sclera will be formed from the outermost layer. (Carlson B 2004).
Eyelids and Lacrimal Glands
At the seventh week, the eyelids will start developing as folds of skin that grow over the cornea. By the end of ninth week they become fused with each other. The eyelashes and the small glands at the margins of the lids begin to differentiate from the common epithelial lamina before the eyelids reopen. (Carlson B 2004). Multiple epithelial buds grow from the lateral surface ectoderm and differentiate into the lacrimal glands. Reopening of the eyelids normally occur at the seventh month of gestation. The lacrimal glands are not fully mature at birth, and newborns typically do not produce tears when crying. The glands begin to function at about 6 weeks (Moore K, 2008).
Molecular Genetic Aspect of Human eye Development.
Master control genes:
Many genes control the eye development and differentiation have been identified. These genes are expressed in early embryogenesis and induce a series of gene expression that is responsible for further development.
The model master control gene for eye development is paired box gene 6 (PAX6). The expression of this gene start on week 6-9 of development (Firsova et al., 2008) and located on chromosome 11p13. See figure (5) for the genomic structure of Pax 6. (Waiet al,. 2002).
Several findings document an important role of Pax6 during early stages of lens induction.
Initially, Pax6 is expressed in the cells that will give rise to the optic vesicle in the anterior neural plate. It is necessary for the activation of Sox2 in the ectoderm and maintaining lens-bias of the surface ectoderm. Pax6 activity is essential for the induction of lens differentiation. Although Pax-6 is not required for maintaining Sox2 expression. Sox2 alone, however, cannot support lens formation in the absence of Pax6. Pax-6 also control the expression of other genes that regulate eye development such as the homeobox genes Six3 and Prox1. Figure (6). (Ruth et al,. 2000)
Pax6 also essential in early retina development. Surprisingly Pax6 function seems to be not essential for the induction of retinal layers differentiation. However, it does play an important role in further steps of retinogenesis (Ruth et al,. 2001). At the optic cup stage, Pax6 is important for cell proliferation and differentiation. Following optic cup formation, Pax6 will be downregulated in the optic stalk and the retinal pigmented epithelium, but retained in the neuroretina. Expression in the neural retina is maintained in the proliferating retinal progenitor cells (RPCs), while it is downregulated in most cells upon differentiation. Pax6 expression maintained in amacrine and ganglion cells in mature retina. This dynamic expression pattern is preserved among vertebrates thus it reflect the important function for Pax6 during retinogenesis and in subtypes of mature neurons (Walther et al., 1991).
Immunohistochemical studies by Nishina (Nishina et al., 1999 ) in human embryo showed that Pax6 is expressed at 6 weeks of gestation on the inner and outer layers of the optic cup, surface ectoderm and the optic stalk. Expression persists from 8 to 10 weeks of conception in the inner and outer neuroblastic retinal layers. At week 21 and 22, Pax6 is restricted to the inner nuclear and ganglion cell layers where amacrine cells and horizontal cells differentiate. This demonstrates the importance of Pax6 functions in maintaining multipotency and proliferation of retinal progenitor cells. However, the cellular mechanism activated by Pax6 still has to be determined. Figure (7) shows normal expression of Pax-6. Mutations in humans prove that Pax6 plays a critical role in eye development (Waiet al,. 2002).
In humans, PAX6 mutations have been recognized in both sporadic and familial cases of aniridia (without iris), was first described by Barrata in 1818 (Graw, 2003). Pax-6 mutaion seen in Peters' anomaly. Both are accompanied by numerous developmental disorders. Heterozygous mutations of PAX-6 result in iris aplasia, ectopia of the pupil, etc. Homozygous mutations in PAX6 will result in anophthalmia with developmental anomalies of the nose and brain. (Firsova et al., 2008).
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Figure (5): Genomic structure of the human PAX6 gene. The two overlapping cosmids cH1-7 and cH1-2 were characterized by restriction mapping and Southern analysis. (Fan ET AL, 2006)
Figure (6): Early expression of Pax6 during early stage of eye development. (Ruth et al., 2001).
Figure (7): Normal expression of Pax-6 mRNA, yellow, during early eye development. Radioactive in situ hybridisation on transverse sections at embryonic ages (A) E8.0; (B) E8.5; (C) E9.25; (D) E9.5; (E) E10.5 and (F) E15.5. Surface ectoderm (se), optic pit (op), floorplate (fp), neural folds (nf),optic vesicle (ov), lens placode (lp), lens pit (pt), optic stalk (os), pigmented retinal epithelium (pre), cornea (cn). (Wang et al., 2001).
Early eye development and optic vesicle formation:
Rx gene(also known as RAX) is important for regional specification of the lateral wall of the forebrain to the optic vesicle. The optic vesicles develop from two lateral patches in the anterior neural plate (Jean et al., 1998).
SHH gene is another essential gene that contributes to the normal eye field separation into two optic vesicles by regulating, initially, its proximo-distal patterning and at later stage the central-to-periphery and dorso-ventral patterning of the optic cup (Adler et al,. 2007). Holoprosencephaly and cyclopia can result from SHH gene mutation (Graw, 2003).
More genes have also been revealed to influence eye field formation and optic vesicle formation and/or evagination. Six3, Lhx2, Six6/Optx2, ET and tll seem to play essential role that could be under the effect of extra-cellular signaling molecules (Bailey et al., 2004)
Table 1 shows the summary of genes involved in development of the eye through the early stages of optic cup.
Table (1): Genes involved in eye development through early optic cup stages.
(Adler R et al., 2007).
Stage of development.
Specification of the eye field
Pax6, Rx, Six3, Lhx2, Six6/Optx2, ET, tll, Hes1. Otx2,
Optic vesicle evagination
Pax6, Rx, tll
Optic vesicle dorso-ventral patterning
Pax6, Rx, Lhx2, Chx10, Otx2, Mitf, Pax2, Vax
Optic vesicle naso-temporal patterning
Pax6, BF1/Foxg1, BF2/Foxd2.
Optic vesicle invagination into an optic cup
Pax6, Lhx2, Hes1
FOX genes family (FOXC1 -FOXE3) involved in eye development. Several studies showed that patients with Axenfeld-Rieger anomaly or iris hypoplasia - which is a dominant disorders that affect the anterior segment of the eye - had mutations in FOXC1. FOXC1 is essential in expressing cornea, sclera, conjunctival epithelium (Graw J, 2003). FOXE3 is also important for eye development. and is expressed with the start of lens placode induction. after the lens placode forms, FoxE3 expression increases and becomes limited to the lens vesicle as it detaches from the surface ectoderm. Gene mutations will result in fusion of the lens and the cornea due to failure of lens vesicle to separate from the ectoderm ( anterior segment malformation) (Graw, 2003).
The human gene cytochrome P450 family 1 (CYP1B1), also have a role in the development of anterior segment. Defects in this gene causing central cornea opacity, associated with adhesion between the cornea and the lens that is seen in Peters anomaly (Graw, 2003).
Rest of genes involved in anterior segment expression summarized in table 2.
Table (2): Other important genes in development of anterior segment. (Graw J 2003, Jean D et al., 1998 and Firsova N et al., 2008).
Tissue of expression.
Result of mutation.
PIXT2 and PITX3
Cornea, lens and retina.
PITX2 mutation associated with Rieger syndrome.
PITX3 mutation cause anterior segment mesenchymal dysgenesis (ASMD).
Lens vesicle, Lens placode and primary lens fibers.
Congenital cataract, microphthalmia, coloboma, anterior segment defect.
Differentiation of lens cells and regulation of the expression of genes encoding crystallins, structural proteins of the lens.
Lens placodes 6 and the anterior part of the neural plate, ganglionic cells and inner nuclear layers of the retina.
Holoprosencephaly, microphthalmia and iris coloboma.
lens placodes and all lens cells.
LIM2, MIP, GJA3, GJA8, and CRY
All lens cells.
Iris and CB development:
Differentiation of the optic cup into non-neuronal/peripheral versus neuronal/central progenitors occurs days before the genesis of the iris and CB. This is expressed by genes Meis1, Meis2, Pax6 and Otx1 and the growth-arrest-specific protein Gas1. (Noa D et al., 2008).
As the iris stroma consists of migratory cells, stromal hypoplasia of the iris or cell-migration failure is a frequent genetic disorder which is known as Axenfeld-Rieger syndrome (ARS).
ARS is autosomal dominant disorder that is characterized by glaucoma, anterior segment defects and other extraocular anomalies. Two main genes mutation occur in ARS. The Forkhead/winged helix transcription factor FOXC1 and bicoid-like homeobox gene PITX2 . Moreover, some studies show that a complete form of ARS resulting from a small deletion on 11p13, where the PAX6 gene located (Graw, 2003).
The Genetic Complexity of Retinogenesis:
The growing optic vesicle contains bipotential progenitors that could give rise to both neural retinal cells (RPE) and retinal progenitor cells (NR) types. Separation of these progenitors to NR and RPE is mediated by other factors. Fibroblast growth factors (FGFs) secreted from the surface ectoderm help NR cell formation, whereas the RPE formation directed by ocular mesenchyme (Ruth et al,. 2001).
Many transcription factors regulate the specification of retinal cell types. The basic helix-loop-helix (bHLH) neural transcription factor and Pax-6 are likely intrinsic factors that play an important role in regulating the retinal neurons cells differentiation (Waiet al,. 2002).
During retinogenesis, Math5 and Mash1 which are neural Transcription Factors (bHLH) genes activated in a subpopulation of retinal progenitor cells. They have strong role in differentiation of retinal progenitor cells toward particular cell fates (Wang et al., 2001). In addition, Mash1 and NeuroD also regulate neuronal subtype specification beside promoting neuronal fate determination. (Cepko C. 1999). During retinal development, bipolar cell differentiation is regulated by Mash1 and the homeobox gene Chx10. NeuroD assist amacrine and rod fates but restricts bipolar cell fates. These studies indicate that the genetic regulatory pathway play essential role in retinal progenitor cells differentiation, but its exact details remain to be elucidated (Waiet al,. 2002).
Additional transcription factors that are expressed before and during retinal differentiation are shown in the table ( 3 ): (Wai W et al,. 2002 and Jean d ET AL., 1998 ).
Table 3. List of human genes involved in retinal development.
Neural retina germinative layer, bipolar cell.
Microphthalmia congenital cataract
Neural retina germinative layer.
Retinal pigment epithelium
Neural retina germinative layer.
T cell lymphoblastic leukemia Alagille syndrome
Renal-coloboma syndrome renal hyperplasia
Retinal pigmented epithelium, ganglion cell layer, neural retina germinative layer.
Outer nuclear layer of the neurosensory retina
Enhanced S cone syndrome
Photoreceptors, cone bipolar cells and cells in the ganglion cell layer in the retina
Ganglion cell layer, inner cell layer, outer cell layer of neural retina.
Extracellular signaling molecules:
Eye development is regulated by signaling molecules which belong to a number of gene families. This family include Wnt, transforming growth factor β (TGF-β), hedgehog (Hh), bone morphogenetic proteins (BMPs) and fibroblast growth factor (FGF). Multiple eye developmental events are controlled by many of these signaling molecules which appears at different stages of eye development (Adler et al,. 2007).
FGF and the Wnt non-canonical pathway control the morphogenetic movements of progenitor cells towards the eye field (Moody, 2004). The non-canonical branch of the Wnt signaling pathway subsequently ensures the integration of progenitor cells in the eye field. However, the canonical/βcatenin branch should be be dowregulated or inhibited so the eye field will differentiate from the diencephalic region (Esteve et al,.2006).
Cyclops (Cyc) gene that is encoding TGF-β family is involved in splitting of the eye fields through the induction of SHH expression (Adler et al,. 2007).
Wnt pathway has been shown as important in the specification of retinal progenitors to the non-neuronal fates of the anterior structures, the iris and ciliary body (Kubo et al., 2003). Lack of Wnt signaling lead to prevention of the expression of peripheral markers such as Collagen-9 and Bmp7 and consequently led to an iris hypoplasia with a severe reduction in muscle size. Co-expression of BMP and Wnt family members in the optic cup periphery shows a possible involvement of these two pathways in the development of the iris and ciliary body and may contribute in the promotion of the non-neuronal fate of the progenitor cells. Furthermore, it should be noticed that BMPs and Wnts may have paracrine effect on the periocular mesenchyme and the morphogenesis of the derivative structures (Noa et al,.2008).
Based upon the inductive signals from adjacent mesenchyme and surface ectoderm, the optic vesicle neuroepithelium is differentiated into retinal pigment epithelium (RPE) and neural retina (NR). Induction of neural retina formation by FGF family members which are expressed in the surface ectoderm (Chow and Lang, 2001). In addition, neural retina itself expresses FGF8 and FGF9 upon contact with the surface ectoderm, both play a role in defining the boundary between NR and RPE (Zhao et al., 2001) .