Injury induces retinal Müller glia of certain cold-blooded vertebrates, but not mammals, to regenerate neurons. To identify gene regulatory networks that reprogram Müller glia into progenitor cells, we profiled changes in gene expression and chromatin accessibility in Müller glia from zebrafish, chick and mice in response to different stimuli. We identified evolutionarily conserved and species-specific gene networks controlling glial quiescence, reactivity and neurogenesis. In zebrafish and chick, transition from the quiescence to reactivity is essential for retinal regeneration, while in mice a dedicated network suppresses neurogenic competence and restores quiescence. Disruption of nuclear factor I (NFI) transcription factors, which maintain and restore quiescence, induces Müller glia to proliferate and generate neurons in adult mice following injury. These findings may aid in designing therapies to restore retinal neurons lost to degenerative diseases.

Highlights d Mouse retinal development was profiled using single-cell RNA-seq d Early and late-stage retinal progenitors are distinct d Primary and neurogenic retinal progenitors are distinct d NFI factors control cell-cycle exit and generation of late-born retinal cell types

Retinoic acid (RA) signaling plays critical roles in diverse cellular processes during nervous system development. In mouse models, the roles for RA signals in telencephalic development remain unclear, partly because of the ambiguity of RA telencephalic sources after E8.75. Here, we have developed a genetic approach that utilizes Cre-lox technology to conditionally express a potent dominant negative retinoid receptor, RAR403, in vivo. This approach blocks RA signaling pathways at the receptor level, enabling the disruption of RA signals in contexts in which the RA source is unknown. RAR403 expression throughout the developing telencephalon causes pronounced hypoplasia resulting from defective proliferation in dorsal telencephalic progenitors and extensive cell death. Furthermore, Nkx2.1(+) progenitors in the medial ganglionic eminence (MGE) are misspecified such that they acquire a subset of lateral ganglionic eminence (LGE)-specific properties at the expense of MGE fates. This genetic approach reveals new roles for RA signaling in telencephalic proliferation, survival and fate specification, and underscores its utility in investigating the function of retinoid signaling pathways throughout peri- and postnatal development.