| First Author | Capecchi MR | Year | 2015 |
| Journal | Nat Commun | Volume | 6 |
| Pages | 8763 | PubMed ID | 26581405 |
| Mgi Jnum | J:228026 | Mgi Id | MGI:5704272 |
| Doi | 10.1038/ncomms9763 | Citation | Capecchi MR, et al. (2015) ASPM regulates symmetric stem cell division by tuning Cyclin E ubiquitination. Nat Commun 6:8763 |
| abstractText | 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. |
