Snail superfamily transcriptional repressors Scratch1 and 2 are essential for maintenance of retinal ganglion cells and normal visual function

Scratch1 and Scratch2 (Scrt1/2) of the Snail superfamily transcriptional repressors are evolutionarily well-conserved from nematodes to humans and are predominantly expressed in the developing central nervous system. However, the in vivo functions and underlying mechanisms of Scratch remain unclear because of the lack of analysis using Scratch- deficient animals. Transcriptional and histological analyses revealed that Scrt1/2 are co-expressed in retinal ganglion cells (RGCs), amacrine cells, and horizontal cells in the mouse retina from early embryonic stages to adulthood. We generated Scrt1 −/− and Scrt2 −/− mice, in which no detectable phenotypic changes were observed in appearance or retinal morphology. Nevertheless, Scrt1/2 double-knockout (DKO) mice of either sex displayed small body size and low postnatal viability, as well as decreased RGC density and thinner optic nerves in the retina. Single-cell RNA sequencing analysis of control and Scrt DKO retinas at embryonic day 17.5 revealed upregulation of the pro-apoptotic gene S100a11 in RGCs. Forced expression of S100a11 in adult mouse retinas induced RGC apoptosis chronically. Consistent with the reduction of RGC density and thinning of optic nerves, Scrt DKO mice showed impaired RGC axonal projections to the accessory optic system (AOS) and consequently exhibited defective optokinetic responses (OKRs). Together, the present study suggests that the repressive regulation of pro-apoptotic and axon guidance genes by mouse Scratch is essential for maintaining RGC survival and normal visual function. Significance Statement Scratch1 and Scratch2 ( Scrt1/2 ) are evolutionarily well-conserved transcriptional repressors that are predominantly expressed in the central nervous system. In the current study, we found that Scrt1/2 were highly expressed in retinal ganglion cells (RGCs). The generation of Scrt DKO mice enabled the analysis of mammalian Scrt1/2 function in vivo for the first time, revealing that Scrt1/2 are essential for systemic growth and viability of mice, RGC survival, and optic nerve projection. Optokinetic responses were impaired in Scrt DKO mice, along with altered optic nerve projections. This study suggests that transcriptional repression mediated by Scrt1/2 is indispensable for RGC survival and normal visual function.