During retinogenesis, fate specification of retinal progenitor cells (RPCs) is regulated by the transcription factor VSX2, which promotes the proliferation and formation of bipolar cells while suppressing rod photoreceptor genesis. Although VSX2 is known to act via binding to cis-regulatory elements, a detailed molecular understanding of this process is missing. In this study, Issam Aldiri and colleagues, using an elaborate array of functional and genetic approaches, demonstrate that VSX2 binds to its own upstream super-enhancer (SE) region, along with PAX6, as part of a positive autoregulatory feedback loop. Here, the authors compare two conserved enhancer regions, EN1 and SE, to which VSX2 binds. Interestingly, VSX2 interactions with these enhancers are spatially and temporally regulated: EN1 binding promotes retinal proliferation and, at a later timepoint, SE interactions drive bipolar cell differentiation. This is exemplified by the fact that EN1, but not SE, mutants display microphthalmia and major embryonic phenotypes. Simultaneously, VSX2, in co-operation with the transcription factor OTX2, represses Prdm1 expression, which is required for rod photoreceptor production, highlighting further circuits of cis-regulatory elements during retinogenesis. Thus, these findings enhance our understanding of how VSX2 functions in the complex gene regulatory networks that drive retinal proliferation and RPC fate specification.
