Mutation of vsx genes in zebrafish highlights the robustness of the retinal specification network

Genetic studies in human and mice have established a dual role for Vsx 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 Vsx functions are also conserved across vertebrates, as mutant models are available only in mammals. To gain insight into vsx function in teleosts, we have generated vsx1 and vsx2 CRISPR/Cas9 double knockouts (vsxKO) in zebrafish. Our electrophysiological and histological analyses indicate severe visual impairment and bipolar cells depletion in vsxKO larvae, with retinal precursors being rerouted toward photoreceptor or Muller glia fates. Surprisingly, neural retina is properly specified and maintained in mutant embryos, which do not display microphthalmia. We show that although important cis-regulatory remodelling occurs in vsxKO 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 Vsx genes regulatory weight varying substantially among vertebrate species.

Automated summary

Genetic studies have shown that Vsx genes play a dual role in retina development, being involved in progenitor specification and determination of bipolar cell fate. However, the extent to which Vsx functions are conserved across vertebrates is still unclear. In this study, Vsx1 and Vsx2 were knocked out in zebrafish embryos using CRISPR/Cas9, resulting in severe visual impairment and depletion of bipolar cells. Surprisingly, the neural retina was properly specified and maintained in mutant embryos. The findings suggest that genetic redundancy is an important mechanism for maintaining the integrity of the retinal specification network.