CHAPTER 41 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 regulators, including PAX6, RX, SIX3 and OTX2, develops the potential to form optic vesicles. Subsequent interactions between mesenchyme and neurectoderm involving expression of the secreted protein SHH at the midline subdivides this eye field region into bilateral domains at the future sites of the eyes (Chow & Lang 2001). Loss of SHH function causes holoprosencephaly and a range of malformations that can include cyclopia. 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 (Saha et al 1992). Vascular tissue of the developing eye may form by local angiogenesis or vasculogenesis of angiogenetic mesenchyme. (Accounts of the development of the eye are given in O’Rahilly 1966 and 1983.)
EMBRYONIC COMPONENTS OF THE EYE
The first morphological sign of eye development is a thickening of the diencephalic neural folds at 29 days postovulation, 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 the period when the rostral neuropore closes, at about 30 days (stage 11), the walls of diencephalon 1 (see Fig. 24.2) begin to evaginate at the optic sulcus, projecting laterally towards the surface ectoderm, so that, by 32 days, the optic vesicles are formed. Failure of the specification and development of the optic vesicle is associated with mutation of several transcriptional regulator genes expressed in the eye field and leads to anophthalmia (absence of the eye) (Graw 2003). The lumen of each optic vesicle is continuous with that of the neuromere diencephalon 1; the vesicle is surrounded by a sheath of mesenchymal cells derived from the head mesenchyme and neural crest. By 31 days, 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 which will become the sensory (neural) retina forms a flat disc of thickened epithelium in close contact with the surface ectoderm; 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. Between 33 and 35 days postovulation, the lens placode and optic vesicle, responding to inductive signalling interactions involving fibroblast growth factors (FGFs) between these two tissues (Chow & Lang 2001), undergo coordinated morphogenesis. The lens placode invaginates, forming a pit which pinches off from the surface ectoderm to form the lens vesicle (Fig. 41.1). The surface ectoderm reforms a continuous layer which will become the corneal epithelium. The lateral part of the optic vesicle invaginates to form a cup: the inner layer (facing the lens vesicle) will become the sensory (neural) retina, and the outer layer, influenced by signals from the surrounding extra ocular mesenchyme, becomes the retinal pigmented epithelium. As a result of these folding movements, what were the apical (luminal) surfaces of the two layers of the cup 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. 41.2). The narrow part of the optic vesicle between the base of the cup and the brain forms the optic stalk. As well as the invagination of the lateral part of the optic vesicle, the ventral surface of the vesicle and distal part of the stalk similarly invaginate, forming a wide groove, the choroid (optic) fissure, through which mesenchyme and the hyaloid artery extend. These infoldings involve differential growth and cell movement, high and levels of proliferation in the inner neuroepithelial layer. 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 is accompanied by a corresponding deficiency in the choroid 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 CHX10, which is important for specification and growth of the neural retina, is one known cause of microphthalmia (Graw 2003).
Fig. 41.1 Development and morphogenesis of the optic vesicle.
(A, B, D, E By courtesy of Kathleen Sulik PhD, Professor, University of North Carolina.)
DIFFERENTIATION OF THE FUNCTIONAL COMPONENTS OF THE EYE
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 regulators, including PAX6 and PAX2, are important for specifying each region (Chow & Lang 2001). 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 around 36 days. In a parallel process, which 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 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 (Fig. 41.2). The development of this pattern is reflected in regional differences in the expression of various genes which encode transcriptional regulators and which 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), which suggests 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, which may, in part, account for the co-involvement of the eye and other organs in syndromes which result from single genetic lesions, e.g. PAX2 mutation causes coloboma and kidney defects, reflecting the sites of expression of the gene (Graw 2003).
