SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron.
A series of transcription factors critical for maintenance of the neural stem cell state have been identified, but the role of functionally important corepressors in maintenance of the neural stem cell state and early neurogenesis remains unclear. Previous studies have characterized the expression of both SMRT (also known as NCoR2, nuclear receptor co-repressor 2) and NCoR in a variety of developmental systems; however, the specific role of the SMRT corepressor in neurogenesis is still to be determined. Here we report a critical role for SMRT in forebrain development and in maintenance of the neural stem cell state. Analysis of a series of markers in SMRT-gene-deleted mice revealed the functional requirement of SMRT in the actions of both retinoic-acid-dependent and Notch-dependent forebrain development. In isolated cortical progenitor cells, SMRT was critical for preventing retinoic-acid-receptor-dependent induction of differentiation along a neuronal pathway in the absence of any ligand. Our data reveal that SMRT represses expression of the jumonji-domain containing gene JMJD3, a direct retinoic-acid-receptor target that functions as a histone H3 trimethyl K27 demethylase and which is capable of activating specific components of the neurogenic program.
Jepsen
Kristen
K
Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, USA. kjepsen@ucsd.edu
Solum
Derek
D
Zhou
Tianyuan
T
McEvilly
Robert J
RJ
Kim
Hyun-Jung
HJ
Glass
Christopher K
CK
Hermanson
Ola
O
Rosenfeld
Michael G
MG
D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D054278:Embryonal Carcinoma Stem Cells; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism
D004268:DNA-Binding Proteins; D006657:Histones; C539130:NCOR2 protein, human; C539131:Ncor2 protein, mouse; C539132:Ncor2 protein, rat; D056985:Nuclear Receptor Co-Repressor 2; D012097:Repressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; D010089:Oxidoreductases, N-Demethylating; D008239:Lysine