title: ASPM regulates symmetric stem cell division by tuning Cyclin E ubiquitination.
abstract: We generate a mouse model for the human microcephaly syndrome by mutating the ASPM locus, and demonstrate a premature exhaustion of the neuronal progenitor pool due to dysfunctional self-renewal processes. Earlier studies have linked ASPM mutant progenitor excessive cell cycle exit to a mitotic orientation defect. Here, we demonstrate a mitotic orientation-independent effect of ASPM on cell cycle duration. We pinpoint the cell fate-determining factor to the length of time spent in early G1 before traversing the restriction point. Characterization of the molecular mechanism reveals an interaction between ASPM and the Cdk2/Cyclin E complex, regulating the Cyclin activity by modulating its ubiquitination, phosphorylation and localization into the nucleus, before the cell is fated to transverse the restriction point. Thus, we reveal a novel function of ASPM in mediating the tightly coordinated Ubiquitin- Cyclin E- Retinoblastoma- E2F bistable-signalling pathway controlling restriction point progression and stem cell maintenance.
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Amir
authors.initials: A
authors.lastname: Pozner
mesh_terms: D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D002455:Cell Division; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D016193:G1 Phase; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C512460:ASPM protein, mouse; D002148:Calmodulin-Binding Proteins; D019927:Cyclin E; D050684:E2F Transcription Factors; D009419:Nerve Tissue Proteins; D016160:Retinoblastoma Protein; D051357:Cyclin-Dependent Kinase 2