Ikaros family proteins redundantly regulate temporal patterning in the developing mouse retina

Temporal identity factors regulate competence of neural progenitors to generate specific cell types in a time-dependent manner, but how they operate remains poorly defined. In the developing mouse retina, the Ikaros zinc-finger transcription factor Ikzf1 regulates production of early-born cell types, except cone photoreceptors. In this study we show that, during early stages of retinal development, another Ikaros family protein, Ikzf4, functions redundantly with Ikzf1 to regulate cone photoreceptor production. Using CUT&RUN and functional assays, we show that Ikzf4 binds and represses genes involved in late-born rod photoreceptor specification, hence favoring cone production. At late stages, when Ikzf1 is no longer expressed in progenitors, we show that Ikzf4 re-localizes to target genes involved in gliogenesis and is required for Mu'' ller glia production. We report that Ikzf4 regulates Notch signaling genes and is sufficient to activate the Hes1 promoter through two Ikzf GGAA-binding motifs, suggesting a mechanism by which Ikzf4 may influence gliogenesis. These results uncover a combinatorial role for Ikaros family members during nervous system development and provide mechanistic insights on how they temporally regulate cell fate output.

Automated summary

Temporal identity factors, such as Ikaros zinc-finger transcription factors Ikzf1 and Ikzf4, play important roles in regulating the production of specific cell types during neural development. Ikzf4 acts redundantly with Ikzf1 during early retinal development to promote cone photoreceptor production, while it is involved in gliogenesis and Müller glia production in the late stages. These findings highlight the combinatorial role of Ikaros family members in neural development and provide insights into the temporal regulation of cell fate output.