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 Müller 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.

Time to see: How temporal identity factors specify the developing mammalian retina.

Understanding how retinal progenitor cells (RPCs) give rise to the variety of neural cell types of the retina has been a question of major interest over the last few decades. While environmental cues and transcription factor networks have been shown to control specific cell fate decisions, how RPCs alter fate output over time to control proper histogenesis remains poorly understood. In recent years, the identification of "temporal identity factors (TIFs)", which control RPC competence states to ensure that the right cell types are produced at the right time, has contributed to increasing our understanding of temporal patterning in the retina. Here, we review the different TIFs identified to date in the mammalian retina and discuss the underlying mechanisms by which they are thought to operate. We conclude by speculating on how identification of temporal patterning mechanisms might support the development of new therapeutic approaches against visual impairments.