Characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice.
Cyclin-dependent kinase 4 (Cdk4) and Cdk6, and later Cdk2, in association with their specific cyclin partners, regulate the G1 to S phase cell cycle transition of mammalian cells by phosphorylation of retinoblastoma (Rb) family proteins. Phosphorylation of Rb results in the release of S-phase specific transcription factors; cell cycle-promoting gene expression, and advancement of the cell cycle. Loss of Cdk4 by homologous-targeted disruption leads to a delay in S-phase entry in serum-stimulated mouse embryo fibroblast (MEF) cultures. Homozygous Cdk4-deficient mice display defects in weight gain, fertility and hypoproliferation of specific endocrine cells of the pituitary and pancreas, the latter of which results in a diabetes-like phenotype. In contrast, inheritance of the p16(Ink4a)-insensitive Cdk4(R24C) mutation leads to spontaneous transformation of MEF cultures in vitro and, in vivo, hyperproliferative disorders that progress to cancer. In this manuscript, we report characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice. We observe that, whereas Cdk4 is dispensable for early pancreatic development, normal Cdk4 expression is critical for optimal growth of the organism. Also, we observe that loss of Cdk4 may result in insulin insensitivity, implicating an additional role of Cdk4 in beta-cell function, in addition to its role in beta-cell proliferation. Further, we demonstrate that loss of Cdk4 leads to an age-dependent defect in spermatogenesis and disruption in the timing of the estrus cycle. Taken together, our results indicate that the overall defects in growth, fertility and pancreatic development in Cdk4-deficient mice may be a combination of cell-type specific defects and altered glucose metabolism, as a result of defects in postnatal pancreatic development.
Mettus
Richard V
RV
Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Rane
Sushil G
SG
D000818:Animals; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics* / Q000378:metabolism; D004822:Epididymis / Q000473:pathology; D030762:Estrous Cycle / Q000235:genetics / Q000378:metabolism; D005260:Female; D007246:Infertility / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D010179:Pancreas / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins; D013737:Testis / Q000473:pathology
D011518:Proto-Oncogene Proteins; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases