PAX6 is the key regulatory gene for eye development. It is a member of the PAX (paired box) family of transcription factors and contains two DNA binding motifs that include a paired domain and a paired type homeodomain. Initially, this transcription factor is expressed in a band in the anterior neural ridge of the neural plate before neurulation begins. At this stage, there is a single eye field that later separates into two optic primordia. The signal for separation of this field is sonic hedgehog (SHH) expressed in the prechordal plate (see Fig. 19.32). SHH expression up-regulates PAX2 in the center of the eye field and down-regulates PAX6. Later this pattern is maintained so that PAX2 is expressed in the optic stalks and PAX6 is expressed in the optic cup and overlying surface ectoderm that forms the lens. As development proceeds, it appears that PAX6 is not essential for optic cup formation. Instead, this process is regulated by interactive signals between the optic vesicle and surrounding mesenchyme and the overlying surface ectoderm in the lens-forming region (Fig. 17.9). Thus, fibro-blast growth factors (FGFs) from the surface ectoderm promote differentiation of the neural (inner layer) retina, while transforming growth factor ft (TGF-ft), secreted by surrounding mesenchyne, directs formation of the pigmented (outer) retinal layer. Downstream from these gene products the transcription factors MITF and CHX10 are expressed and direct differentiation of the pigmented and neural layer, respectively (Fig. 17.9). Thus, the lens ectoderm is essential for proper formation of the optic cup such that without a lens placode no cup invagination occurs.
Differentiation of the lens is dependent upon PAX6, although the gene is not responsible for inductive activity by the optic vesicle. Instead, PAX6 acts autonomously in the surface ectoderm to regulate lens development (Fig. 17.10). The process begins with PAX6 expression in the neural plate that upregulates the transcription factor SOX2 and also maintains PAX6 expression in the prospective lens ectoderm. In turn, the optic vesicle secretes BMP-4, which also upreg-ulates and maintains SOX2 expression as well as expression of LMAF, another transcription factor. Next, the expression of two homeobox genes, SIX3 and
Figure 17.9 Drawing showing molecular regulation of epithelial-mesenchymal interactions responsible for patterning eye development. A. Once PAX6 establishes the eye field, fibroblast growth factors (FGFs), secreted by surface ectoderm (SE) in the prospective lens-forming region overlying the optic vesicle, promote differentiation of the neural retinal layer; while members of the transforming growth factor ß (TGF-ß) family, secreted by surrounding mesenchyme, promote differentiation of the pigmented retinal layer. These external signals cause regionalization of the inner and outer layers of the optic cup and upregulate downstream genes, including CHX10 and MITF, that regulate continued differentiation of these structures (B and C). In addition to its role in determining the eye fields, PAX6 specifies the lens placode (LP) region (B) and is also important for retinal development.
Figure 17.10 Schematic showing the cascade of gene expression responsible for early stages of lens development.
PROX1, is upregulated by PAX6, while BMP-7 expression in the lens ectoderm is increased to maintain expression of SOX2 and PAX6. Finally, the combined expression of PAX6, SOX2, and LMAF initiates expression of genes responsible for formation of lens crystalline proteins, while PROX1 expression regulates genes controlling cell proliferation.
Coloboma may occur if the choroid fissure fails to close. Normally this fissure closes during the seventh week of development (Fig. 17.8). When it does not, a cleft persists. Although such a cleft is usually in the iris only—coloboma iridis (Fig. 17.11 A)—it may extend into the ciliary body, the retina, the choroid, and the optic nerve. Coloboma is a common eye abnormality frequently associated with other eye defects. Colobomas (clefts) of the eyelids may also occur. Mutations in the PAX2 gene have been linked with optic nerve colobomas and may play a role in the other types as well. Renal defects also occur with mutations in PAX2 as part of the renal coloboma syndrome (see Chapter 14).
The iridopupillary membrane (Fig. 17.11 B) may persist instead of being resorbed during formation of the anterior chamber.
In congenital cataracts the lens becomes opaque during intrauterine life. Although this anomaly is usually genetically determined, many children of mothers who have had German measles (rubella) between the fourth and seventh weeks of pregnancy have cataracts. If the mother is infected after the seventh week of pregnancy, the lens escapes damage, but the child may be deaf as a result of abnormalities of the cochlea.
The hyaloid artery may persist to form a cord or cyst. Normally the distal portion of this vessel degenerates, leaving the proximal part to form the central artery of the retina.
In microphthalmia the eye is too small; the eyeball may be only two-thirds of its normal volume. Usually associated with other ocular abnormalities,
microphthalmia frequently results from intrauterine infections such as cy-tomegalovirus and toxoplasmosis.
Anophthalmia is absence of the eye. In some cases histological analysis reveals some ocular tissue. The defect is usually accompanied by severe cranial abnormalities.
Congenital aphakia (absence of the lens) and aniridia (absence of the iris) are rare anomalies that are due to disturbances in induction and formation of tissues responsible for formation of these structures. Mutations in PAX6 result in aniridia and may also contribute to anophthalmia and microphthalmia.
Cyclopia (single eye) and synophthalmia (fusion of the eyes) comprise a spectrum of defects in which the eyes are partially or completely fused (Fig. 17.12). The defects are due to a loss of midline tissue that may occur as early as days 19 to 21 of gestation or at later stages when facial development is initiated. This loss results in underdevelopment of the forebrain and frontonasal prominence. These defects are invariably associated with cranial defects, such as holoprosencephaly, in which the cerebral hemispheres are partially or completely merged into a single telencephalic vesicle. Factors affecting the midline include alcohol, mutations in sonic hedgehog, (SHH) and abnormalities in cholesterol metabolism that may disrupt SHH signaling (see Chapter 19).
Figure 17.12 Synophthalmia. The eyes are fused because loss of midline structures prevented the eye fields from separating. Such babies also have severe cranial defects, including holoprosencephaly.
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