Onecut1 and onecut2 function redundantly to determine multiple cell fates during mouse retinal development
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Background: Gene regulation plays essential roles in cell differentiation during development. Onecut (Oc) transcription factors, characterized by a single "cut" domain and an atypical homeodomain, are expressed in different regions of the developing central nervous system, including the retina. Previously, we have shown that the onecut members Oc1 and Oc2 are present in early retinal progenitor cells, developing retinal ganglion cells (RGCs), and both developing and mature horizontal cells (HCs). We have also shown that Oc1 -null mice have an 80% reduction in HC development but no defect in other retinal cell types. Objective: To determine whether the lack of defects in other cell types in Oc1 -null retinas is due to redundancy between Oc1 and Oc2. Methods: Oc1 and Oc2 were deleted in the retina by crossing Oc1-flox and Oc2-flox alleles with the Six3-Cre transgenic mouseline. Single and double-null retinas were analyzed by histology, immunohistochemistry, electron microscopy, and RNA-Seq. Results: Like Oc1 -null retinas, Oc2 -null retinas exhibit defects in only HCs, with ~ 50% reduction in their development. In contrast, Oc1/Oc2 double-null retinas are defective in all four early-born cell types, with HC and starburst amacrine cell development being completely abolished and RGC and cone development being significantly reduced. In addition, double-null retinas have perturbed proportions of various RGC subtypes and increased numbers of S-cone subtype at the expense of M-cone subtype. Transcriptome profiling reveals that Oc1 and Oc2 act by promoting horizontal and cone fate-determining genes, repressing precocious expression of pro-rod genes, and promoting some ganglion cell-specific genes and repressing others. Conclusion: The milder phenotype of Oc1 -null retinas is indeed due to redundancy between Oc1 and Oc2. The two factors promote early-born cell fates and suppress one late-born cell fate, the rod fate, by regulating common downstream genes in the developing retina. They may function similarly in other regions of the developing central nervous system.