RFC1regulates the expansion of neural progenitors in the developing zebrafish cerebellum

Abstract

SummaryDNA replication and repair are basic yet essential molecular processes for all cells.RFC1encodes the largest subunit of the Replication Factor C (RFC), which is a clamp-loader during DNA replication and repair. Intronic repeat expansion inRFC1has recently been associated with so-calledRFC1-related disorders, which mainly encompass late-onset cerebellar ataxias. However, the mechanisms that make certain tissues more susceptible to defects in these universal pathways remain mysterious. In this study, we provide the first investigation ofRFC1gene functionin vivousing zebrafish. We showed thatRFC1is expressed in neural progenitor cells within the developing cerebellum and that it is necessary to maintain these cells’ genomic integrity during neurogenic maturation. Accordingly,RFC1loss-of-function leads to a severe cerebellar phenotype due to impaired neurogenesis of both Purkinje and granule cells. Our data thus point to a specific role ofRFC1in the developing cerebellum, paving the way for a better understanding of the pathogenic mechanisms underlyingRFC1-related disorders.