title: Genetic rescue of Cdk4 null mice restores pancreatic beta-cell proliferation but not homeostatic cell number.
abstract: Lack of Cdk4 expression in mice leads to insulin-deficient diabetes and female infertility owing to a reduced number of pancreatic beta cells and prolactin-producing pituitary lactotrophs, respectively. Cdk4 null mice display also reduced body and organ size. Here, we show that Cdk4 is essential for the postnatal proliferation of pancreatic beta cells but not for embryonic neogenesis from ductal epithelial cells. Re-expression of endogenous Cdk4 in beta cells and in the pituitary gland of Cdk4 null mice restores cell proliferation and results in fertile and normoglycemic animals, thus, demonstrating that the proliferation defects in these cellular populations are cell autonomous because of the lack of Cdk4 expression. However, these mice remain small in size, indicating that this phenotype is not because of pancreatic- or pituitary-mediated endocrine defects. This phenotype is a consequence of reduced cell numbers rather than reduced cell size. Thus, mammalian Cdk4 is not only involved in controlling proliferation of specific cell types but may play a wider role in establishing homeostatic cell numbers.
authors.affiliation: Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martín
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Hunt
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.forename: Rocío
authors.initials: R
authors.lastname: Sotillo
authors.forename: Fanny
authors.initials: F
authors.lastname: Néhmé-Pélluard
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.forename: Albert F
authors.initials: AF
authors.lastname: Parlow
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.forename: Sagrario
authors.initials: S
authors.lastname: Ortega
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
mesh_terms: D000818:Animals; D001824:Body Constitution / Q000235:genetics; D002455:Cell Division / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010641:Phenotype; D011518:Proto-Oncogene Proteins
chemical_list: D011518:Proto-Oncogene Proteins; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases