Effects of prenatal exposure to ethanol on the cyclin-dependent kinase system in the developing rat cerebellum.
Prenatal exposure to ethanol inhibits neurogenesis in the developing cerebellum. Cyclin-dependent kinases (CDKs) are a family of protein kinases that play multiple roles in the regulation of cell proliferation, differentiation and survival. The activity of CDKs is positively regulated by CDK activators, cyclins, and negatively regulated by CDK inhibitors (CDKIs). We hypothesize that impaired cerebellar development induced by gestational ethanol exposure is mediated by disruption of the CDK system. Pregnant rats were fed ad libitum with an ethanol-containing liquid diet (Et) or pair-fed an isocaloric control diet (Ct). Cerebella were collected from pups (postnatal day (P) 0 through P21) and examined for CDK, cyclin, or CDKI expression using a quantitative immunoblotting procedure. In Ct-treated rats, the expression of CDK2 and its activator, cyclin A, paralleled the pattern of granule cell proliferation. Prenatal ethanol exposure produced a significant down-regulation of CDK2/cyclin A expression. Although the amounts of CDK4/CDK6 and their activator, cyclin D2, did not oscillate during postnatal development, their expression in Et-treated pups was significantly (P<0.05) higher than in controls. The expression of a CDK inhibitor, p27(Kip), was inversely correlated to proliferation of cerebellar granule progenitors. Prenatal ethanol exposure caused the down-regulation of p27(Kip) between P0 and P21. Thus, prenatal exposure to ethanol disturbed the expression of cell cycle machineries in the postnatal cerebellum. This may account for the teratogenic effects of ethanol on the developing cerebellum.
Li
Zheng
Z
Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Robert C. Byrd Health Science Center, P.O. Box 9177, Morgantown, WV 26506, USA.
Miller
Michael W
MW
Luo
Jia
J
D020268:Alcohol-Induced Disorders, Nervous System / Q000201:enzymology* / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002531:Cerebellum / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D018844:Cyclin-Dependent Kinases / Q000187:drug effects* / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000201:enzymology* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D020318:Rats, Long-Evans; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology
D000431:Ethanol; D018844:Cyclin-Dependent Kinases