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REST corepressors RCOR1 and RCOR2 and the repressor INSM1 regulate the proliferation–differentiation balance in the developing brain

Significance Nervous system development involves a delicate balance between neural progenitor proliferation and neuronal differentiation. Repressors and corepressors each affect this balance, but in many cases, existence of the complexes in vivo has not been shown. Here, we identify a repressor/corepressor complex in embryonic brain consisting of Insulinoma-associated 1 (INSM1) and the RE1 Silencing Transcription factor (REST) corepressors RCOR1 and RCOR2. Elimination of RCOR1 and RCOR2, or INSM1, robustly promotes neural proliferation over neuronal and oligodendrocyte differentiation. Further, their elimination results in overexpression of REST, a direct target gene of INSM1. Normalizing REST levels in the RCOR1/2-deficient brain partially restores aberrant brain morphology. Our results identify a repressor complex required for critical events during normal brain development. The transcriptional events that lead to the cessation of neural proliferation, and therefore enable the production of proper numbers of differentiated neurons and glia, are still largely uncharacterized. Here, we report that the transcription factor Insulinoma-associated 1 (INSM1) forms complexes with RE1 Silencing Transcription factor (REST) corepressors RCOR1 and RCOR2 in progenitors in embryonic mouse brain. Mice lacking both RCOR1 and RCOR2 in developing brain die perinatally and generate an abnormally high number of neural progenitors at the expense of differentiated neurons and oligodendrocyte precursor cells. In addition, Rcor1/2 deletion detrimentally affects complex morphological processes such as closure of the interganglionic sulcus. We find that INSM1, a transcription factor that induces cell-cycle arrest, is coexpressed with RCOR1/2 in a subset of neural progenitors and forms complexes with RCOR1/2 in embryonic brain. Further, the Insm1−/− mouse phenocopies predominant brain phenotypes of the Rcor1/2 knockout. A large number of genes are concordantly misregulated in both knockout genotypes, and a majority of the down-regulated genes are targets of REST. Rest transcripts are up-regulated in both knockouts, and reducing transcripts to control levels in the Rcor1/2 knockout partially rescues the defect in interganglionic sulcus closure. Our findings indicate that an INSM1/RCOR1/2 complex controls the balance of proliferation and differentiation during brain development.