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Loss of Cdk2 and Cdk4 Induces a Switch from Proliferation to Differentiation in Neural Stem Cells.
MedLine Citation:
PMID:  22532528     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
During neurogenesis, cell cycle regulators play a pivotal role in ensuring proper proliferation, cell cycle exit, and differentiation of neural precursors. However, the precise role of cyclin-dependent kinases (Cdks) in these processes is not well understood. We generated Cdk2 and Cdk4 double knockout (DKO) mice and found a striking ablation of the intermediate zone and cortical plate in the mouse embryonic brain. When neural stem cells (NSCs) were isolated and analyzed, DKO NSCs proliferated comparable to wild type as Cdk1 now binds to cyclin D1 and E1 and assumes the role vacated by the loss of Cdk2 and Cdk4 in phosphorylating Rb. Although compensation was sufficient for the maintenance of self-renewal and multi-lineage potential, DKO NSCs displayed an altered cell cycle profile and were more prone to neuronal differentiation. This was manifested in vivo as a marked reduction in S phase length and an increased tendency for neurogenic divisions that prevented proper expansion of the basal progenitor pool. Our data thus demonstrate the induction of neurogenic divisions in the absence of critical mediators of G1/S transition -- Cdk2 and Cdk4, and highlight their evolutionary importance in the determination of cortical thickness. Highlight #1 Loss of Cdk2 & Cdk4 results in enhanced neuronal differentiation Highlight #2 Cdk1 complexes compensate for the loss of Cdk2 and Cdk4 in NSCs Highlight #3 Cdk2 and Cdk4 are not essential for the proliferation of NSCs Highlight #4 Cdk2 and Cdk4 mediates the expansion of basal progenitors.
Authors:
Shuhui Lim; Philipp Kaldis
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-24
Journal Detail:
Title:  Stem cells (Dayton, Ohio)     Volume:  -     ISSN:  1549-4918     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-4-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9304532     Medline TA:  Stem Cells     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 AlphaMed Press.
Affiliation:
Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos #3-09, Singapore 138673, Republic of Singapore.
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