TY - JOUR
T1 - REST corepressors RCOR1 and RCOR2 and the repressor INSM1 regulate the proliferation- differentiation balance in the developing brain
AU - Monaghan, Caitlin E.
AU - Nechiporuk, Tamilla
AU - Jeng, Sophia
AU - McWeeney, Shannon K.
AU - Wang, Jianxun
AU - Rosenfeld, Michael G.
AU - Mandel, Gail
N1 - Funding Information:
We are grateful for the support and helpful ongoing discussions of the work by Dr. John Rubenstein (University of California, San Francisco) and Dr. Huilan Yao (H3 Biomedicine).We thank Dr. Carmen Birchmeier at the Max Delbrück Center for Molecular Medicine for generously providing us with INSM1 antibody and Susan Kim for assisting with image analysis. This work was supported by NIH Grants NS022518 (to G.M.), UL1TR000128 (to S.K.M.), and NS093066 and DK09949 (to M.G.R.).
PY - 2017/1/17
Y1 - 2017/1/17
N2 - 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.
AB - 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.
KW - INSM1
KW - Neurogenesis
KW - RCOR1
KW - RCOR2
KW - REST
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U2 - 10.1073/pnas.1620230114
DO - 10.1073/pnas.1620230114
M3 - Article
C2 - 28049845
AN - SCOPUS:85009812493
SN - 0027-8424
VL - 114
SP - E406-E415
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 3
ER -