The microRNA, miR9-2, Regulates Progenitor Competence and Müller Glial Homeostasis in Retinal Development and Disease

Abstract

Proper retinal cell fate specification and regulation of homeostasis is essential to establishing a functional visual circuit. MicroRNAs (miRNAs) have been implicated in these processes, yet the individual miRNAs that contribute to this regulation have not been well-defined. The miR9-2 regulatory locus has been linked to retinal disease and related phenotypes is active in human retinal progenitor cells (RPCs) and Müller glia (MG). To explore the function of miR9-2 in the developing and mature retina, I used transgenic miR9-2 knockout (KO) mouse models, single-nucleus RNA-sequencing, and histology. In germline miR9-2 KO retinas, I found that loss of miR9-2 in progenitors delayed the production of retinal cell types, led to MG disorganization, and generated hybrid neuronal-glial cells. Further, MG-specific KO of miR9-2 led to the rapid loss of recombined Müller cells, and disruptions to metabolic-, synaptic-, and cell-cell junction-related genes. I identified transcriptional targets of miR9-2 and found that miR9-2 can directly regulate several cell fate-determining transcription factor networks. Overall, these results indicate that miR9-2 is critical for controlling the timing of RPC competence and normal gliogenesis and that its dysregulation may contribute to retinal disease.