Geminin regulates neuronal differentiation by antagonizing Brg1 activity.
Precise control of cell proliferation and differentiation is critical for organogenesis. Geminin (Gem) has been proposed to link cell cycle exit and differentiation as a prodifferentiation factor and plays a role in neural cell fate acquisition. Here, we identified the SWI/SNF chromatin-remodeling protein Brg1 as an interacting partner of Gem. Brg1 has been implicated in cell cycle withdrawal and cellular differentiation. Surprisingly, we discovered that Gem antagonizes Brg1 activity during neurogenesis to maintain the undifferentiated cell state. Down-regulation of Gem expression normally precedes neuronal differentiation, and gain- and loss-of-function experiments in Xenopus embryos and mouse P19 cells demonstrated that Gem was essential to prevent premature neurogenesis. Misexpression of Gem also suppressed ectopic neurogenesis driven by Ngn and NeuroD. Gem's activity to block differentiation depended upon its ability to bind Brg1 and could be mediated by Gem's inhibition of proneural basic helix-loop-helix (bHLH)-Brg1 interactions required for bHLH target gene activation. Our data demonstrate a novel mechanism of Gem activity, through regulation of SWI/SNF chromatin-remodeling proteins, and indicate that Gem is an essential regulator of neurogenesis that can control the timing of neural progenitor differentiation and maintain the undifferentiated cell state.
Seo
Seongjin
S
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Herr
Anabel
A
Lim
Jong-Won
JW
Richardson
Genova A
GA
Richardson
Helena
H
Kroll
Kristen L
KL
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation; D002460:Cell Line; D004247:DNA / Q000235:genetics; D004265:DNA Helicases; D004330:Drosophila / Q000166:cytology / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D064248:Geminin; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D051379:Mice; D008959:Models, Neurological; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D016296:Mutagenesis; D009420:Nervous System / Q000196:embryology / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation; D014981:Xenopus; D029867:Xenopus Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology
D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; C577998:GMNN protein, Xenopus; C577995:GMNN protein, human; D064248:Geminin; C577997:Gmnn protein, mouse; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D029867:Xenopus Proteins; D004247:DNA; C084108:SMARCA4 protein, human; C513194:Smarca4 protein, mouse; D004265:DNA Helicases; C490245:GEM protein, human; D020559:Monomeric GTP-Binding Proteins