Kavli Affiliate: Seth Blackshaw
| Authors: Selin Bekir, Johanna L. Hopf, Theresa Paul, Valerie M. Wiemer, Tyler Santander, Henri E. Skinner, Anna Rada, Friedrich G. Woermann, Thilo Kalbhenn, Barry Giesbrecht, Christian G. Bien, Olaf Sporns, Michael S. Gazzaniga, Lukas J. Volz and Michael B. Miller
| Summary:
Evolutionary adaptation to diurnal vision in ground squirrels has led to the development of a cone-dominant retina, in stark contrast to the rod-dominant retinas of most mammals. The molecular mechanisms driving this shift remain largely unexplored. Here, we perform single-cell RNA sequencing (scRNA-Seq) and chromatin accessibility profiling (scATAC-Seq) across developmental retinal neurogenesis in the 13-lined ground squirrel (13LGS) to uncover the regulatory basis of this adaptation. We find that 13LGS cone photoreceptors arise not only from early-stage neurogenic progenitors, as seen in rod-dominant species like mice, but also from late-stage neurogenic progenitors. This extended period of cone generation is driven by a heterochronic shift in transcription factor expression, with cone-promoting factors such as Onecut2, Pou2f1, and Zic3 remaining active in late-stage progenitors, and factors that promote cone differentiation such as Thrb, Rxrg, and Mef2c expressed precociously in late-stage neurogenic progenitors. Functional analyses reveal that Zic3 and Mef2c are sufficient to promote cone photoreceptor and respress rod specification, and act through species-specific regulatory elements that drive their expression in late-stage progenitors. These results demonstrate that evolutionary modifications to gene regulatory networks underlie the development of cone-dominant retinas and provide insight into mechanisms of sensory adaptation and potential strategies for cone photoreceptor regeneration in vision disorders.