RPE Proliferation as a Novel Cause of Uveal Coloboma

Article: Genetic Clues in Uveal Coloboma
Source: Vanderbilt University Medical Center
Published: April 27, 2021

Proliferation is upregulated in the RPE layer in the Nf2 knockout optic cup.
The ventral-most region harboring the optic fissure shows cells (red)
in the G2/M stage of cell division increased in B compared to A.
Arrows indicate a thickened RPE layer in F compared to E.

Colobomas are congenital ocular malformations resulting from the incomplete closure of the optic fissure during embryonic development. Although most commonly visualized as incomplete formation of the iris, colobomas can occur in a variety of ocular structures, including the lens, choroid, retina, optic disc, and eyelid. Depending on the eye tissue affected and the extent of malformation, colobomas can cause blindness. Prior research demonstrated that mutations in the gene encoding neurofibromin 2 (NF2), a tumor suppressor protein important in tissue development and regeneration, can cause colobomas, among other contributing causes. Researchers studying the role of the gene Nf2 found that silencing the gene in developing mouse eyes led to proliferation of the retinal pigment epithelium (RPE) in the optic fissure region, with RPE cells not forming a monolayer but multiple layers. The cellular crowding from RPE proliferation prevents the cells from transitioning to a cuboidal shape. This leads to improper alignment and orientation of the RPE cells, failure of optic fissure fusion/closure, and ultimately persistent coloboma. The researchers also note that, interestingly, these cells retain their RPE character, rather than transforming into other tissues of the retina. The authors write, "Our findings indicate that limiting proliferation particularly in the RPE layer is a critical mechanism during OF [optic fissure] closure." They hope that studying the underlying mechanism of RPE proliferation during development may help to understand factors preventing regeneration of adult RPE and inform therapeutics for RPE-related eye diseases.

My rating of this study: ⭐⭐⭐

Sun WR, Ramirez S, Spiller KE, et al. "Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye." Human Molecular Genetics.  29(20):3373–3387. 15 October 2020. https://doi.org/10.1093/hmg/ddaa228