Lens

Thickening of the lens placode can be seen on gestational day 27 in the human (see Fig. 1-10). Before its contact with the optic vesicle, the surface ectoderm must become competent to respond to lens inducers. It then receives inductive signals from the anterior neural plate, so that it gains a "lens-forming bias" specified for lens formation. Complete lens differentiation requires both inductive signals from the optic vesicle and an inhibitory signal from head neural crest to suppress any residual lens-forming bias in head ectoderm adjacent to the lens.38 In the chick, a tight extracellular matrix-mediated adhesion between the optic vesicle and the surface ectoderm has been described.47,57,69 This anchoring of the mitotically active surface ectoderm results in cell crowding, cell elongation, and formation of the thickened placode.119 Adhesion between the optic vesicle and the lens placode is thought to ensure alignment of the lens in the visual axis.15 Although adhesion between the optic vesicle and surface ectoderm exists, electron microscopic studies have demonstrated that there is no direct cell contact.22,49,108 The basement membranes of the optic vesicle and the surface ectoderm remain separate and intact throughout the contact period. Experimental studies have demonstrated a requirement for functional PAX6 gene in both the optic vesicle and surface ectoderm to mediate lens placode induction.23 The BMP4 gene, which is present only in the optic vesicle, is also required for lens induction.35

The lens placode invaginates forming the hollow lens vesicle (Figs. 1-11, 1-12). The size of the lens vesicle is determined by the area of contact of the optic vesicle and the surface ectoderm. Lens vesicle detachment from the surface ectoderm occurs on day 33 (7-9 mm) and is the initial event leading to the formation of the chambers of the eye. This process of separation is accompanied by active migration of epithelial cells out of the keratolenticular stalk or junction,37 cellular necrosis, and base-

ment membrane breakdown.36 Although apoptosis (programmed cell death) is a normal feature of lens vesicle separation, excessive and persistent cell death is associated with aphakia in the lap mouse mutant.8

Induction of a small lens vesicle that fails to undergo normal separation from the surface ectoderm is one of the characteristics of teratogen-induced anterior segment malformations described in animal models.24,28,81,102 In the mouse mutant (dyl), this failure of lens vesicle separation is caused by a mutation in the FoxE3 gene that promotes survival and proliferation while preventing differentiation of the lens epithelium.18 AP-2 transcription factors also influence lens vesicle separation as well as causing mis-expression of PAX6 and MIP26 genes.109 Anterior lenticonus, anterior capsular cataracts, and anterior segment dysgenesis with keratolenticular adhesions (Peters' anomaly) may result from faulty keratolenticular separation. Further discussion of anterior segment dysgenesis follows. Arrest of lens development at the lens stalk stage results in aphakia in mutant mice (ak mutation). In addition to aphakia, affected eyes exhibit absence of a pupil and abnormalities in the iris, ciliary body, and vitreous.40,41

The hollow lens vesicle consists of a single layer of epithelial cells with cell apices directed toward the center of the sphere. Following detachment from the surface ectoderm, the lens vesicle is surrounded by a basal lamina, the future lens capsule. Abnormalities in this basement membrane may result in involution of the lens vesicle, resulting in later aphakia.8 At approximately 37 days gestation, primary lens fibers form from elongation of the posterior lens epithelium of the lens vesicle (Fig. 1-14).51 The retinal anlage promotes primary lens fiber formation in the adjacent lens epithelial cells. Experimental in vivo rotation of the lens vesicle in the chick eye by 180° results in elongation of the lens epithelial cells nearest the presumptive retina, regardless of the orientation of the transplanted lens.31 Thus, the retina develops independently from the lens although the lens appears to rely upon the retina for cytodifferentiation. In the mouse, the Prox1 and Maf genes have been demonstrated to mediate lens fiber elongation.88,110 As these posterior epithelial cells lengthen to fill the lumen of the lens vesicle, they lose their nucleus and most organelles.14 Upregulation of lens-specific proteins, CP49 and CP95, is demonstrated after closure of the lens stalk.51 The primitive lens filled with primary lens fibers is the embryonic lens nucleus. After the epithelial cells

Surface ectoderm

Cuboidal -epithelium (future lens epithelium)

Elongating primary lens fibers

Hyaloid artery/ primary vitreous

Neurosensory retina

FIGURE 1-14. Formation of the embryonic lens nucleus and primary lens fibers at approximately 7 weeks. Note that mesenchyme (M) of neural crest origin surrounds the optic cup. The posterior lens epithelial cells (located nearest the developing retina, R) elongate, forming the primary lens fibers (L). The anterior epithelium remains cuboidal and becomes the anterior epithelium in the adult. The optic fissure is now closed.

FIGURE 1-14. Formation of the embryonic lens nucleus and primary lens fibers at approximately 7 weeks. Note that mesenchyme (M) of neural crest origin surrounds the optic cup. The posterior lens epithelial cells (located nearest the developing retina, R) elongate, forming the primary lens fibers (L). The anterior epithelium remains cuboidal and becomes the anterior epithelium in the adult. The optic fissure is now closed.

of the posterior lens elongate to form the fibers of the embyronal nucleus, they eventually separate from the posterior capsule; therefore, there is an absence of epithelial cells on the posterior capsule. In the adult, the embryonic nucleus is the central round, slightly dark sphere inside the Y sutures. There are no sutures within the embryonal nucleus. The lens fibers have extensive interdigitations with a relative absence of extracellular space. Anterior lens epithelial cells (nearest the corneal anlage) remain cuboidal and become the permanent lens epithelium, which is mitotic throughout life, giving rise to future secondary fetal and adult cortical lens fibers.

After the embryonic nucleus is formed, secondary lens fibers develop from anterior epithelial cells to form the fetal nucleus. The anterior epithelial cells migrate to the periphery of the lens (lens equator), where they elongate and differentiate into lens fibers. This region of the lens is called the lens bow. These secondary lens fibers elongate anteriorly and posteriorly around the embryonic nucleus to meet at the anterior and posterior poles of the lens (Fig. 1-15). The lens fibers exhibit surface interdigitations with relative lack of extracellular space. Unlike more mature cortical lens fibers that have tapered ends, these fetal lens fibers (secondary lens fibers) have blunt tips, so when they meet they form a faint adherence or "suture." This meeting of the secondary lens fiber ends results in two Y sutures, the anterior upright Y suture and the posterior inverted Y suture

FIGURE 1-15. Diagram of secondary lens fibers and Y sutures. Secondary lens fibers elongate at the equator to span the entire lens, from the anterior Y suture to the posterior Y suture. The anterior Y suture is upright and the posterior Y suture is inverted.

(Fig. 1-15). The fetal nucleus consists of the secondary lens fibers and can be clinically identified as that part of the central lens that is inside the Y sutures but outside the embryonic nucleus. The lens differentiates under the influence of many growth factors, including FGF, IGF, PDGF, and TGF, and genes become active encoding cytoskeletal proteins (filensin, phakinin, vimentin, nestin), structural proteins (crystallins), and membrane proteins.39,118 Abnormal initiation and differentiation of secondary lens fibers have been demonstrated in the Cat2 and Cat3 mutant mouse strains. These eyes exhibit abnormalities limited to the lens, unlike the aphakia mutant eyes, which have malformations of the anterior segment and vitreous and folding of the retina.40

At birth, the lens is almost entirely made up of lens nucleus with minimal lens cortex. Lens cortex continues to develop from the anterior epithelial cells postnatally and throughout life. Congenital cataracts that occur as a result of abnormal formation of primary or secondary lens fibers would be expected to be localized in the nuclear region between the Y sutures. Abnormal lens vesicle separation from the surface ectoderm would be associated with defects in anterior epithelium or lens capsule and may cause anterior polar cataracts. Incomplete regression of the pupillary membrane can be associated with (secondary) anterior lens opacities. A defect of the surface ectoderm or basement membrane could result in cataracts associated with anterior or posterior lenticonus.

Tunica Vasculosa Lentis

The lens receives nutrition and blood supply from the hyaloid artery, a branch of the primitive ophthalmic artery. The hyaloid artery first enters the eye through the optic fissure (see Fig. 1-12) and then becomes incorporated into the center of the optic nerve as the optic fissure closes. The hyaloid vessels form a network around the posterior lens capsule and then anastomose anteriorly with the network of vessels in the pupillary membrane (Fig. 1-16). The pupillary membrane consists of vessels and mesenchyme that overlie the anterior lens capsule (see Development of Anterior Segment). This hyaloid vascular network that forms around the lens is called the tunica vasculosa lentis. The hyaloid vasculature reaches its greatest development at approximately 10 weeks gestation. The tunica vasculosa lentis and hyaloid artery regress during the end of the fourth month of

FIGURE 1-16. Drawing of a 2-month-old fetal eye shows the hyaloid vascular system and tunica vasculosa lentis.

gestation. The clinical lens anomaly, Mittendorfs dot, is a small (1-2 mm) area of fibrosis on the posterior capsule and is probably a manifestation of incomplete regression of the hyaloid artery where it attaches to the posterior capsule. The regression of the pupillary membrane begins during the sixth month and is usually complete by the eighth month. Persistent pupillary membranes result from incomplete regression. These iris strands may connect to an anterior polar cataract (Fig. 1-17) or area of corneal endothelial fibrosis.

CORNEA AND ANTERIOR CHAMBER

The anterior margins of the optic cup advance beneath the surface ectoderm and its subjacent mesenchyme following lens vesicle detachment at approximately day 33 of gestation. The surface ectoderm overlying the optic cup and lens represents the presumptive corneal epithelium-, it secretes a thick matrix producing the primary cornea stroma.43 This acellular material consists of collagen fibers, hyaluronic acid, and glycosaminoglycans. Neural crest cells migrate between the surface ectoderm and

FIGURE 1-17. Photograph of persistent pupillary membrane with small central anterior polar cataract.

optic cup using the basal lamina of the lens vesicle as a substrate or scaffold.11 Hydration of hyaluronic acid helps to create the space for cellular migration.105 This loosely arranged neural crest cell-derived mesenchyme initially fills the future anterior chamber and gives rise to the corneal stroma, corneal endothe-lium, the anterior iris stroma, the ciliary muscle, and most of the structures of the iridocorneal angle. Separation of the corneal mesenchyme (neural crest cell origin) from the lens (surface ectoderm origin) results in formation of the anterior chamber. Mesenchymal tissue surrounds the lens and forms the tunica vasculosa lentis and is continuous anteriorly with the pupillary membrane. Capillaries within the tunica vasculosa lentis anastomose with the hyaloid vascular system. The vascular endothe-lium appears to be the only component of the anterior segment that is of mesodermal origin, as even the vascular smooth muscle cells and pericytes are of neural crest origin.55,64

The anterior corneal stroma remains acellular and gives rise to Bowman's membrane, which underlies the corneal epithelium. Although the corneal epithelium is of surface ectodermal origin, Bowman's membrane is a condensation of anterior corneal stroma that is of neural crest cell origin. Type I collagen fibrils and fibronectin secreted by the developing keratocytes (neural crest cell origin) form the secondary corneal stroma. Subsequent dehydration of the corneal stroma results in loss of much of the fibronectin and a 50% reduction in thickness of the stroma.44,65 The endothelium plays an important role in the dehydration of the stroma. Patches of endothelium become confluent during the early part of the fourth month of gestation and develop zonulae occludentes at their apices by the middle of the fourth month of gestation.115 By the sixth month of gestation, Descemet's membrane and endothelium are structurally and functionally present and, at this time, the cornea achieves relative transparency. Proteoglycans containing keratan sulfate chains play a role in generating and maintaining corneal transparency.34

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