The Retinoblastoma family member p107 regulates the rate of progenitor commitment to a neuronal fate.
The Retinoblastoma protein p107 regulates the neural precursor pool in both the developing and adult brain. As p107-deficient mice exhibit enhanced levels of Hes1, we questioned whether p107 regulates neural precursor self-renewal through the repression of Hes1. p107 represses transcription at the Hes1 promoter. Despite an expanded neural precursor population, p107-null mice exhibit a striking reduction in the number of cortical neurons. Hes1 deficiency rescues neurosphere numbers in p107-null embryos. We find that the loss of a single Hes1 allele in vivo restores the number of neural precursor cells at the ventricular zone. Neuronal birthdating analysis reveals a dramatic reduction in the rate of neurogenesis, demonstrating impairment in p107(-/-) progenitors to commit to a neuronal fate. The loss of a single Hes1 allele restores the number of newly generated neurons in p107-deficient brains. Together, we identify a novel function for p107 in promoting neural progenitor commitment to a neuronal fate.
Vanderluit
Jacqueline L
JL
Department of Cellular and Molecular Medicine, Ottawa Health Research Institute, Neuroscience Program, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Wylie
Crystal A
CA
McClellan
Kelly A
KA
Ghanem
Noel
N
Fortin
Andre
A
Callaghan
Steve
S
MacLaurin
Jason G
JG
Park
David S
DS
Slack
Ruth S
RS
D000483:Alleles; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011401:Promoter Regions, Genetic; D050720:Retinoblastoma-Like Protein p107 / Q000172:deficiency* / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism*; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D018809:Proliferating Cell Nuclear Antigen; D050720:Retinoblastoma-Like Protein p107; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse