Extrinsic regulation of retinal neurogenesis by the retinal pigment epithelium – RETINEXT

The construction of the nervous system requires that the proper number and types of neurons are generated by neural progenitor cells in specific locations, at precise developmental times. Defects in these processes will result in abnormal formation of neuronal circuits with functional consequences that constitute the cause of neurodevelopmental diseases such as albinism. Indeed, all forms of albinism show visual deficits that result from alterations in the developing neural retina, originating from defects in the retinal pigment epithelium (RPE), a layer of epithelial cells that surround the neural retina. Here, we will take advantage of this feature to study how neurogenesis is regulated by extrinsic factors coming from surrounding cells. Most genes in albinism are related to melanosomes and melanin synthesis, but a recently identified gene has been involved in albinism-like retinal and optic nerve defects but without defect of the melanin pathway (FHONDA syndrome). This interesting candidate may thus unveil downstream processes linking melanogenesis to neurogenesis regulation. The protein involved in FHONDA syndrome is SNAT8, an amino acid transporter whose function is not well characterized. Here, we propose to characterize its subcellular localization and transport and/or sensor function. Furthermore, using in vivo (mouse) and in vitro (RPE cells and retinal organoids) models, combined with loss of function by CRISPR/Cas9 to mimic mutations found in both diseases, we will characterize the role of SNAT8 in the RPE and the ciliary margin zone as well as its effect on neurogenesis and its link with albinism. The deciphering of the cellular and molecular mechanisms underlying these two rare diseases will shed new light on the processes of visual system development.