title: REST corepressors RCOR1 and RCOR2 and the repressor INSM1 regulate the proliferation-differentiation balance in the developing brain.
abstract: 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.
authors.affiliation: Vollum Institute, Oregon Health and Science University, Portland, OR 97239.
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Monaghan
authors.affiliation: Vollum Institute, Oregon Health and Science University, Portland, OR 97239.
authors.forename: Tamilla
authors.initials: T
authors.lastname: Nechiporuk
authors.affiliation: Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239.
authors.forename: Sophia
authors.initials: S
authors.lastname: Jeng
authors.affiliation: Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239.
authors.forename: Shannon K
authors.identifier: 0000-0001-8333-6607
authors.initials: SK
authors.lastname: McWeeney
authors.affiliation: Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093.|Department of Medicine, University of California, San Diego, La Jolla, CA 92093.|School of Life Sciences, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Beijing 100029, China.
authors.forename: Jianxun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093.|Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.affiliation: Vollum Institute, Oregon Health and Science University, Portland, OR 97239; mandelg@ohsu.edu.
authors.forename: Gail
authors.initials: G
authors.lastname: Mandel
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D056970:Co-Repressor Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D000099229:RE1-Silencing Transcription Factor
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C477059:Insm1 protein, mouse; C000589468:Rcor1 protein, mouse; C485650:Rcor2 protein, mouse
keywords: INSM1; RCOR1; RCOR2; REST; neurogenesis