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Embryology, Optic Cup
Introduction
Eye development is a complex, multifactorial process organized in both temporal and spatial patterns during embryogenesis. PAX6 is the master control gene, modulated by various signaling pathways governing optic vesicle induction, patterning, and ocular structural specification. Cellular differentiation involves neuroectoderm formation of the optic cup, surface ectoderm-derived lens and anterior segment structures, and neural crest contribution to corneal, trabecular, scleral, and optic nerve connective tissues. The optic cup plays a central role in ocular development, contributing to the formation of all major structures of the globe, with the exception of the lens. Conditions such as congenital glaucoma, retinal detachment, and coloboma are associated with defects of the optic cup or its associated structures and may result in significant visual impairment. Understanding ocular embryogenesis provides a basis for elucidating the pathogenesis of congenital ocular diseases.
Development
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Development
Development of the primitive eye begins at approximately week 3 of gestation with the emergence of the optic sulcus from periocular mesenchyme. The optic sulci are bilateral invaginations on both sides of the anterior neural tube at the level of the diencephalon. Progressive deepening of the sulci leads to the formation of optic pits, followed by transformation into optic vesicles as extension toward the surface ectoderm occurs. Surface ectoderm and optic vesicles both secrete extracellular matrix and establish adhesion between the 2 structures. Continued outward expansion of the optic vesicles shifts the proximal attachment to the forebrain into the optic stalk. Migration of neural crest cells is facilitated by the optic vesicles, with a contribution to subsequent ocular development.
At approximately week 5 of gestation, a portion of the optic vesicle undergoes auto-invagination, forming a 2-layered optic cup. Asymmetric invagination results in the formation of a groove along the inferior margin. This structure is designated the optic fissure, permitting entry of early vasculature and periocular mesenchyme into the developing eye. Closure of the optic fissure occurs by the end of week 6.[1][2][3][4]
The 2 layers of the optic cup constitute a continuous tissue that bends at a hinge point termed the "optic cup lip," which delineates the border between the outer pigmented layer and the inner neural layer.[5] The anterior portion of the optic cup gives rise to the pars caeca retinae.[6] Subsequent development of this structure leads to the formation of the ciliary body, iris, and pupillary muscles.[7] The posterior portion of the optic cup forms the retina.[8] The outer layer of the optic cup differentiates into the retinal pigmented epithelium. The inner layer of the optic cup differentiates into the outer nuclear layer, containing rods and cones, the inner nuclear layer, containing bipolar cells, and the ganglion cell layer, containing ganglion cells. Axonal growth into the optic stalk begins during week 7 of gestation, and completion of optic nerve development occurs by week 8.
Cellular
Neuroectodermal cells comprise the optic cup.[9] Direct derivatives of the optic cup are described in the preceding section. However, embryologic origins of additional ocular structures are relevant. Surface ectoderm contributes to the development of the lens, conjunctiva, eyelids, and corneal epithelium. The optic cup lip forms the adult iris margin. Neural crest cells give rise to the corneal endothelium, trabecular meshwork, scleral fibroblasts, connective fascia of extraocular muscles, and meninges of the optic nerve.
Molecular Level
Multiple genes interact during the development of the primitive eye, consistent with the embryogenesis of other organ systems. In ocular development, PAX6 functions as the primary regulatory gene while WNT (wingless-related integration site) and FGF (fibroblast growth factor) signaling provide supportive roles during optic vesicle development.[10][11][12] Sonic hedgehog (Shh) signaling is another key regulator of ocular embryogenesis and mediates suppression of PAX6 expression.[13] Inhibition of Shh signaling results in dysregulated PAX6 expression and cyclopia. Conversely, increased Shh signaling results in loss of ocular structures. Retinoic acid also plays an essential role in ocular development, primarily through paracrine regulation of mesenchymal tissue surrounding the optic cup. Retinoic acid deficiency leads to anterior segment malformations and may result in blindness.
However, the interplay between genes and molecular signaling factors is highly complex and extends beyond the scope of this article. Additional genes involved in ocular development include, but are not limited to, PITX2, PITX3, FOXC1, FOXE3, LMX1B, GPR48, TFAP2A, and TFAP2B.[14][15]
Function
The optic cup gives rise to the entire globe and its associated internal structures, with the exception of the lens (see Image. Development of the Embryonic Eye). Retinal development includes the formation of 10 layers containing rods, cones, bipolar cells, amacrine cells, and horizontal cells, along with the organized synaptic interactions among these neuronal populations that process photic input into visual perception.
Clinical Significance
Defects in optic cup embryogenesis carry broad clinical significance because the optic cup gives rise to multiple ocular structures. A classic example is coloboma, a developmental defect characterized by the absence of tissue within a part of an ocular structure. Coloboma is thought to result from the failed closure of the optic fissure. The condition may involve most ocular structures and is most commonly associated with defects of the iris, cornea, retina, optic nerve, or choroid. Association with microphthalmia is well documented, with coloboma accounting for up to 2% of blindness in adults and up to 11% of blindness in children.[16] The mechanism underlying co-occurrence with microphthalmia is unclear but may relate to globe ectasia secondary to coloboma formation.[17][18]
Axenfeld-Rieger syndrome (ARS) is a rare genetic condition that may result from defects affecting the optic cup.[19][20] ARS is an autosomal dominant disorder with multiple effects on the anterior segment and may lead to glaucoma.[21] Numerous abnormalities may be present in ARS, with manifestations occurring either in combination or in isolation. Findings are generally classified into 3 categories: iris, corneal, and chamber angle abnormalities.
Iris defects include hypoplasia, corectopia, and polycoria.[22] Posterior embryotoxon is the most common corneal sign of ARS but is not present in all affected patients. Still, detection of posterior embryotoxon warrants evaluation for ARS. In the chamber angle, iris strands may bridge from the iridocorneal angle to the trabecular meshwork. A major mutation associated with ARS involves the transcription factor PITX2. A specific G-protein-coupled receptor, GPR48, expressed extensively in the optic cup, is thought to regulate PITX2.[23] Therefore, GPR48 mutations may result in ARS and contribute to glaucoma in affected populations.
Defects in optic cup development contribute to a spectrum of rare ocular diseases. Complex interactions between embryologic tissue types involved in ocular formation, including neuroectodermal, neural crest, and surface ectoderm derivatives, influence structural development. Conditions affecting neural crest– or surface ectoderm–derived structures may be modified by abnormal neuroectodermal signaling. A comprehensive discussion of rare diseases influenced by neuroectodermal signaling without primary neuroectodermal structural defects is beyond the scope of this article.
Morning glory syndrome is another rare anomaly potentially related to optic cup dysgenesis.[24] Clinical presentation may include retinal detachment, a glial tuft at the optic nerve head, and microphthalmos.[25]
Retinoic acid is essential for proper optic cup development. Accordingly, deficiency or mutations affecting retinoic acid signaling result in abnormal ocular development, ranging from relatively mild disorders such as fundus albipunctatus to severe conditions such as Matthew-Wood syndrome or Leber congenital amaurosis.[26]
In summary, the optic cup is a key embryologic structure responsible for the formation of multiple ocular structures within the globe. Optic cup–derived signaling also contributes to the development of additional intraocular and extraocular structures. Dysgenesis results in a broad spectrum of disorders, including retinal detachment, glaucoma, and anterior segment dysgenesis.
Media
(Click Image to Enlarge)
Development of the Embryonic Eye. This transverse section of a 48-hour chick embryo head shows the early formation of the optic cup and lens. Key structures include the invaginating ectoderm forming the lens rudiment and the differentiation of the retinal layers.
Henry Vandyke Carter, Public Domain, via Wikimedia Commons
References
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