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Development of the eye
The development of the eye involves a series of inductive interactions between neighbouring tissues in the embryonic head. These are the neurectoderm of the forebrain (which forms the sensory retina and accessory pigmented structures), the surface ectoderm (which forms the lens and the corneal epithelium) and the intervening neural crest mesenchyme (which contributes to the fibrous coats of the eye and to tissues of the anterior segment of the eye). A broad anterior domain of neurectoderm, characterized by the activation of several homeobox-containing transcriptional regulator genes, including PAX6 , RAX , SIX3 and OTX2 , and the repression of caudalizing Wnt signalling, develops the potential to form optic vesicles. Subsequent interactions between mesenchyme and neurectoderm, involving midline expression of the gene ( SHH ) encoding the secreted protein sonic hedgehog, subdivides this eyefield region into bilateral domains at the future sites of the eyes ( ). Loss of SHH function causes holoprosencephaly and a range of anomalies that can include cyclopia, due to incomplete separation of the prosencephalon ( ).
In three-dimensional culture of murine embryonic stem cells supplemented with the correct growth factors and Matrigel® (to promote basement membrane formation), but in the absence of surface ectoderm or lens epithelium, a neuroepithelial vesicle develops and undergoes dynamic shape change to form a two-layered optic cup ( ). The tissue so formed demonstrated interkinetic nuclear migration and a stratified architecture similar to that of postnatal retina, including appropriate synapses. Similar results, i.e. production of retinal architecture and retinal pigment epithelial cells, have been reported using human embryonic stem cells ( , ).
The parallel process of lens determination appears to depend on a brief period of inductive influence that spreads through the surface ectoderm from the rostral neural plate and elicits a lens-forming area of the head. Reciprocal interactions that are necessary for the complete development of both tissues take place as the optic vesicle forms and contacts the potential lens ectoderm ( , , ). The vascular tissue of the developing eye forms by local angiogenesis or vasculogenesis of angiogenic mesenchyme ( ). Development of the choroidal vasculature is followed by the (temporary) fetal hyaloid vasculature and then the retinal vasculature. (For further reading see , .)
Embryonic Components of the Eye
The first morphological sign of eye development is a thickening of the diencephalic neural folds in stage 10 (28–29 days postfertilization, see Fig. 23.2 ), when the embryo has seven to eight somites. This optic primordium (eye field) extends on both sides of the neural plate and crosses the midline at the primordium chiasmatis. A slight transverse indentation, the optic sulcus, appears in the inner surface of the optic primordium on each side of the brain. During rostral neuropore closure in stage 11 the walls of the neuromere diencephalon 1 (see Fig. 14.2 ) begin to evaginate at the optic sulcus, projecting laterally towards the surface ectoderm and by stage 13 (postfertilization days 31–33), the optic vesicles are formed. Failure of the specification and development of the optic vesicle is associated with mutation of several transcriptional regulatory genes expressed in the eye field and leads to anophthalmia (absence of the eye) ( ). Each optic vesicle is surrounded by a sheath of mesenchymal cells derived from the head mesenchyme and neural crest; its lumen is continuous with that of diencephalon 1. Regional differentiation is apparent in each of the source tissues of the eye. The optic vesicle is visibly differentiated into its three primary parts. At the junction with the diencephalon, a thick-walled region marks the future optic stalk; laterally, the tissue that will become the sensory (neural) retina forms a flat disc of thickened epithelium in close contact with the surface ectoderm; and the thin-walled part that lies between these regions will later form the pigmented layer of the retina (retinal pigmented epithelium). The area of surface ectoderm that is closely apposed to the distal optic vesicle thickens to form the lens placode, and the mesenchymal sheath of the vesicle begins to show signs of angiogenesis. During stage 14 (postfertilization days 33–34), the lens placode and optic vesicle undergo coordinated morphogenesis. Filopodia tether the presumptive optic and lens vesicles to coordinate epithelial invagination. The lens placode invaginates, forming a pit that pinches off from the surface ectoderm to form the lens vesicle ( Fig. 15.1 ). The surface ectoderm reforms a continuous layer that will become the corneal epithelium. The lateral part of the optic vesicle invaginates to form a cup, which is incompletely formed and open at the ventral surface (optic fissure); the inner layer (facing the lens vesicle) will become the sensory (neural) retina, and the outer layer, influenced by signals from the surrounding extraocular mesenchyme, becomes the retinal pigmented epithelium. As a result of these folding movements, what had been the apical (luminal) surfaces of the presumptive neural retina and retinal pigmented epithelium of the optic vesicle now face one another across a much-reduced lumen, the intraretinal space. The pigmented layer becomes attached to the mesenchymal sheath, but the junction between the pigmented and sensory layers is less firm and is the site of pathological detachment of the retina. The two layers are continuous at the lip of the cup ( Fig. 15.2 ). The narrow part of the optic vesicle between the base of the cup and the brain forms the optic stalk. The distal part of the optic stalk also invaginates, forming a wide groove, the choroid (optic) fissure, through which mesenchyme migrates and differentiates to form the ingressing hyaloid artery. These infoldings involve differential growth, changes in cell shape, cell movement and high levels of proliferation in the inner neuroepithelial layer. The hyaloid artery forms part of the vasculature of the eye. It transiently supplies the developing lens and the inner part of the retina until a retinal vasculature forms and eventually regresses by apoptosis ( ).
As growth proceeds, the fissure closes and the artery is included in the distal part of the stalk. The fusion process is characterized by apoptosis at the margins of the fissure. Failure of the optic fissure to close is a rare anomaly that may be accompanied by a corresponding deficiency in the choroid, retina and iris (congenital coloboma) and is often associated with microphthalmia (small eyes). Reduced growth of the optic cup caused by mutation of the homeobox gene VSX2 , important for specification and growth of the neural retina, is one known cause of microphthalmia ( ). Anophthalmia, microphthalmia and coloboma are also associated with mutation of the SOX2 gene.
Differentiation of the Functional Components of the Eye
The developments just described bring the embryonic components of the eye into the spatial relationships necessary for the passage of light into the globe and onto the retina. The next phase of development involves further patterning and phenotypic differentiation in order to develop the specialized structures of the adult organ needed for focusing and sensing of light.
The optic cup becomes patterned, from the base to the rim, into regions with distinct functions. Several secreted factors, including bone morphogenetic proteins (BMP), retinoic acid and SHH, and transcriptional regulator genes, including PAX6 and PAX2 , are important for specifying each region ( , ). The outer layer of the optic cup remains as a thin layer of cells, which begin to acquire pigmented melanosomes and form the pigmented epithelium of the retina at stage 17. In a parallel process that begins before invagination, the cells of the inner layer of the cup proliferate to form a thick pseudostratified neuroepithelium, the future neural retina, over the base and sides of the cup. The peripheral region around the lip of the cup extends, and is further differentiated into the components of the prospective iris at the rim, and the ciliary body a little further back, adjacent to the neural retina (see Fig. 15.2 ). The development of this pattern is reflected in regional differences in the expression of various genes that encode transcriptional regulators and that are therefore likely to play key roles in controlling and coordinating development. Distinct sets of genes are expressed prior to and during overt cell-type differentiation. For example, PAX6 is expressed in the prospective ciliary and iris regions of the optic cup; individuals heterozygous for mutations in PAX6 lack an iris (aniridia), suggesting a causal role for this gene in the development of the iris. The genes expressed in the eye are also often active at a variety of other specific sites in the embryo. This may, in part, account for the co-involvement of the eye and other organs in syndromes that result from single genetic lesions, e.g. PAX2 mutation causes coloboma and kidney defects ( ).
Developing neural retina
The developing neural retina consists of an outer nuclear zone, which contains dividing neuroepithelial retinal progenitor cells, and an inner marginal zone, which is initially devoid of nuclei. At about stage 16 the cells of the nuclear zone invade the marginal zone, and by stage 18 the nervous stratum of the retina consists of inner and outer neuroblastic layers. Cell lineage analyses have shown that seven retinal cell types are all derived from a common multipotential retinal progenitor cell that undergoes mitosis at the apical (ventricular) surface. Different types of retinal cells are born (i.e. cease dividing) in a conserved sequence during development: ganglion cells, amacrine cells, cone photoreceptors and horizontal cells develop early, whereas bipolar cells, rod photoreceptors and Müller glial cells develop later ( ). Newly born cells migrate from the apical (ventricular) surface to the appropriate cell layer in the developing retina, establishing its characteristic laminar structure. The developing ganglion cell layer first separates from the neuroblastic layers by formation of the inner plexiform layer. The inner nuclear layer, containing developing amacrine, horizontal, bipolar and Müller glial cells, is then separated from the outer nuclear layer, containing the developing rod and cone photoreceptors, by the formation of the outer plexiform layer. Mature retinal neurones first appear in the central part of the retina. By postmenstrual weeks 29–32 all the named layers of the retina can be identified. The photoreceptor cells continue to differentiate after birth, generating an array of increasing resolution and sensitivity; the macula does not reach maturity until 15–45 months after birth ( ).
The divergent differentiation of the pigmented and sensory layers of the retina from the initially bipotential neuroepithelium of the optic vesicle involves activation of region-specific regulatory genes, e.g. VSX2 in the presumptive neural retina and MITF in the presumptive pigmented epithelium ( ). Patterning by gene expression is an important aspect of establishing regional identity of the optic cup and the subsequent maturation of these respective tissues. Soluble factors from the retina elicit the polarized distribution of plasma membrane proteins and the formation of tight junctions in the pigmented epithelium. Neural retinal differentiation is mediated by several growth factors, including fibroblast growth factors, SHH and retinoic acid. Basic helix–loop–helix proneural transcriptional regulatory genes also play a central role in regulating retinal cell fate. However, the pigmented epithelium initially retains the potential to become neural retina and will do so if the embryonic retina is wounded, demonstrating the plasticity of the early commitment to pigment epithelium or neural retinal fate.
The retinal vasculature forms by the aggregation of spindle-shaped cells (vascular mesenchymal cells) that emanate from the optic disc by postmenstrual week 15 and form vascular cords, consistent with vessel formation by vasculogenesis, which give rise to the inner plexus of the retina. Vessel formation in the temporal and peripheral retina occurs by angiogenesis. New vessel segments sprout by endothelial cell migration from pre-existing vessels and grow tangentially by angiogenesis into the neuroepithelium ( ). Three parallel interconnected vascular networks located in the nerve fibre and plexiform layers develop with arteries and veins entering and exiting through the optic nerve. The foveal area never develops a retinal vasculature ( ).
Optic nerve
The optic nerve develops from the optic stalk. The centre of the optic cup, where the optic fissure is deepest, will later form the optic disc, at the transition zone where the neural retina is continuous with the corresponding invaginated cell layer of the optic stalk; the developing axons of the ganglion cells, therefore, pass directly into the wall of the stalk and convert it into the optic nerve. Retinal ganglion cell axons projecting into the stalk promote the optic stalk neuroepithelium to differentiate into astrocytes. Myelination of the axons within the optic nerve begins shortly before birth but the process is not completed until some time later. The optic chiasma is formed by the meeting and partial decussation of the axons within the two optic nerves in the ventral part of the lamina terminalis (at the junction of the telencephalon with the diencephalon in the floor of the third ventricle). Beyond the chiasma, the axons continue as the optic tracts, and pass principally to the lateral geniculate bodies and to the superior tectum of the midbrain. Multiple axonal guidance molecules that influence both intraretinal and chiasmal axon guidance have been identified ( ). Graded expression molecules (members of the Eph family of receptor tyrosine kinase receptors and ephrin ligands) provide spatial identity to cells in the retina and target cells in the midbrain, and are important for the topographic mapping of retinal ganglion cell axons to form a projection map that is representative of visual input.
Ciliary body
The ciliary body is a compound structure. Its epithelial components are derived from the region of the inner layer of the retina, between the iris and the neural retina, and the adjacent outer layer of pigmented epithelium. The cells here differentiate in close association with the surrounding mesenchyme to form highly vascularized folds that secrete aqueous fluid into the anterior segment of the eye.
The inner surface of the ciliary body forms the site of attachment of the lens. The outer layer is associated with smooth muscle derived from mesenchymal cells in the choroid that lie between the anterior scleral condensation and the pigmented ciliary epithelium.
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