Filamin a regulates neural progenitor proliferation and cortical size through Wee1-dependent Cdk1 phosphorylation.
Cytoskeleton-associated proteins play key roles not only in regulating cell morphology and migration but also in proliferation. Mutations in the cytoskeleton-associated gene filamin A (FlnA) cause the human disorder periventricular heterotopia (PH). PH is a disorder of neural stem cell development that is characterized by disruption of progenitors along the ventricular epithelium and subsequent formation of ectopic neuronal nodules. FlnA-dependent regulation of cytoskeletal dynamics is thought to direct neural progenitor migration and proliferation. Here we show that embryonic FlnA-null mice exhibited a reduction in brain size and decline in neural progenitor numbers over time. The drop in the progenitor population was not attributable to cell death or changes in premature differentiation, but to prolonged cell cycle duration. Suppression of FlnA led to prolongation of the entire cell cycle length, principally in M phase. FlnA loss impaired degradation of cyclin B1-related proteins, thereby delaying the onset and progression through mitosis. We found that the cdk1 kinase Wee1 bound FlnA, demonstrated increased expression levels after loss of FlnA function, and was associated with increased phosphorylation of cdk1. Phosphorylation of cdk1 inhibited activation of the anaphase promoting complex degradation system, which was responsible for cyclin B1 degradation and progression through mitosis. Collectively, our results demonstrate a molecular mechanism whereby FlnA loss impaired G2 to M phase entry, leading to cell cycle prolongation, compromised neural progenitor proliferation, and reduced brain size.
Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Gewei
G
Lian
Jie
J
Lu
Jianjun
J
Hu
Jingping
J
Zhang
Sally H
SH
Cross
Russell J
RJ
Ferland
Volney L
VL
Sheen
D000367:Age Factors; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D003285:Contractile Proteins / Q000172:deficiency / Q000378:metabolism*; D056744:Cyclin B1 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian; D064448:Filamins; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen; D051379:Mice; D008822:Mice, Transgenic; D008831:Microcephaly / Q000235:genetics; D008840:Microfilament Proteins / Q000172:deficiency / Q000378:metabolism*; D058953:Neural Stem Cells / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D054091:Periventricular Nodular Heterotopia / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D018797:Cell Cycle Proteins; D003285:Contractile Proteins; D056744:Cyclin B1; D004268:DNA-Binding Proteins; C491199:EOMES protein, human; D064448:Filamins; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D020825:T-Box Domain Proteins; C492271:Tbr1 protein, mouse; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C499348:Wee1 protein, mouse; D016203:CDC2 Protein Kinase; D001973:Bromodeoxyuridine