Mutation of <i>vsx</i> genes in zebrafish highlights the robustness of the retinal specification network.

Abstract

Genetic studies in human and mice have established a dual role for <i>Vsx</i> genes in retina development: an early function in progenitors' specification, and a later requirement for bipolar-cells fate determination. Despite their conserved expression patterns, it is currently unclear to which extent <i>Vsx</i> functions are also conserved across vertebrates, as mutant models are available only in mammals. To gain insight into <i>vsx</i> function in teleosts, we have generated <i>vsx1</i> and <i>vsx2</i> CRISPR/Cas9 double knockouts (<i>vsx</i>KO) in zebrafish. Our electrophysiological and histological analyses indicate severe visual impairment and bipolar cells depletion in <i>vsx</i>KO larvae, with retinal precursors being rerouted toward photoreceptor or Müller glia fates. Surprisingly, neural retina is properly specified and maintained in mutant embryos, which do not display microphthalmia. We show that although important <i>cis</i>-regulatory remodelling occurs in <i>vsx</i>KO retinas during early specification, this has little impact at a transcriptomic level. Our observations point to genetic redundancy as an important mechanism sustaining the integrity of the retinal specification network, and to <i>Vsx</i> genes regulatory weight varying substantially among vertebrate species.