Disease-associated microRNA, miR-9-2, is required for the timing of retinal progenitor cell competence and the maintenance of Müller glial identity

The development of vision is dependent upon precise regulation of cell fate specification. In the mammalian retina, a single pool of multipotent progenitor cells becomes competent to produce the seven major retinal cell classes in distinct but overlapping windows. MicroRNAs (miRNAs) have been implicated in controlling retinal progenitor competence and risk for retinal disease, but it is still unclear which individual miRNAs drive this regulation. Using immunohistochemistry and single-nuclei RNA-sequencing of miR-9-2 enhancer and miR-9-2 knockout mice, we find that specific disruption of miR-9-2, one of three mammalian miR-9 paralogs, delays the emergence of late-born retinal cell classes and leads to misspecification of Müller glial cells to a hybrid neuronal-glial fate. Further, we identify transcription factors and gene regulatory networks directly regulated by miR-9-2 during this process. Thus, this study provides insight into the regulation of the timing of retinal progenitor competence and the risk for retinal disease.