Optic cup morphogenesis across species and related inborn human eye defects

Abstract

The vertebrate eye is shaped as a cup, a conformation that optimizes vision and is acquired early in development through a process known as optic cup morphogenesis. Imaging living, transparent teleost embryos and mammalian stem cell-derived organoids has provided insights into the rearrangements that eye progenitors undergo to adopt such a shape. Molecular and pharmacological interference with these rearrangements has further identified the underlying molecular machineries and the physical forces involved in this morphogenetic process. In this Review, we summarize the resulting scenarios and proposed models that include common and species-specific events. We further discuss how these studies and those in environmentally adapted blind species may shed light on human inborn eye malformations that result from failures in optic cup morphogenesis, including microphthalmia, anophthalmia and coloboma.

Keywords: Anophthalmia; Cavefish; Gene regulatory networks; Human; Mammals; Microphthalmia; Neural retina; Organoids; Retina pigment epithelium; Zebrafish.

Fig. 1.

Schematic representation of vertebrate eye morphogenesis according to a species-specific schedule. (A) Steps of eye morphogenesis from the initial optic vesicle (OV) to a fully formed optic cup (OC). Lens tissue is depicted in green; neural derivatives in orange. The fully formed lens (L) is represented in blue. LE, lens ectoderm; LP, lens placode; NR, neural retina; OC, optic cup; OF, optic fissure; ON, optic nerve; OS, optic stalk; pRPE, presumptive retinal pigment epithelium; RPE, retinal pigment epithelium. (B) Timelines of eye development in different vertebrate species. (C) Graph representing the optic cup volume relative to that of zebrafish in the different depicted species: (from the right) human, mouse, chicken, medaka and zebrafish.

Fig. 2.

Comparison between teleost and mammalian optic cup morphogenesis. (A,B) Schematic representations of the zebrafish (A) and mouse (B) transition from optic vesicle to optic cup (OC). The dashed outlines indicate the shape changes that each cell type undergoes as it acquires the identity of neural retina (NR), retinal pigmented epithelium (RPE) and hinge cells. (C,D) Schematic representations of a section through the zebrafish (C) and human (D) OC, illustrating the differences observed in RPE cell proliferation (green nuclei). LP, lens placode.

Fig. 3.

Inborn eye malformations and possible interactions among causative defective proteins. (A) Schematic representation of the eye in individuals affected by microphthalmia, anophthalmia or ventral coloboma. (B) STRING analysis of proteins encoded by genes responsible for microphthalmia, anophthalmia and coloboma (MAC). Many proteins are potentially functionally connected, with SOX2 acting as the principal node.