title: Loss of oocytes due to conditional ablation of Murine double minute 2 (Mdm2) gene is p53-dependent and results in female sterility.
abstract: Murine double minute 2 and 4 (Mdm2, Mdm4) are major p53-negative regulators, preventing thus uncontrolled apoptosis induction in numerous cell types, although their function in the female germ line has received little attention. In the present work, we have generated mice with specific invalidation of Mdm2 and Mdm4 genes in the mouse oocyte (Mdm2(Ocko) and Mdm4(Ocko) mice), to test their implication in survival of these germ cells. Most of the Mdm2(Ocko) but not Mdm4(Ocko) mice were sterile, with a dramatic reduction of the weight of ovaries and genital tract, a strong increase in follicle-stimulating hormone and luteinizing hormone serum levels, and a reduction of anti-mullerian hormone serum levels. Histological analyses revealed an obvious decrease of the number of growing follicles beyond the primary stage in Mdm2(Ocko) ovaries in comparison to controls, with a pronounced increase in the apparition of primary atretic follicles, most being devoid of oocyte. Similar phenotypes were observed with Mdm2(Ocko) Mdm4(Ocko) ovaries, with no worsening of the phenotype. However, we failed to detect any increase in p53 level in mutant oocytes, nor any other apoptotic marker, introgression of this targeted invalidation in p53-/- mice restored the fertility of females. This study is the first to show that Mdm2, but not Mdm4, has a critical role in oocyte survival and would be involved in premature ovarian insufficiency phenotype.
authors.affiliation: Laboratoire de Développement des Gonades, INSERM U967, CEA/DSV/iRCM/SCSR/LDG, Univ Paris Diderot, Sorbonne Paris Cité, Fontenay-Aux-Roses, France.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Livera
authors.affiliation: Laboratoire Biologie Cellulaire et Microscopie Electronique, Faculté Médecine, University François Rabelais, Tours, France.|Faculty of Bioengineering and Bioinformatics, Moscow State University, Russia.
authors.forename: Rustem
authors.initials: R
authors.lastname: Uzbekov
authors.affiliation: INRA, UMR85 Physiologie de la Reproduction et des Comportements, Nouzilly, France.|CNRS, UMR6175 Physiologie de la Reproduction et des Comportements, Nouzilly, France.|Université François Rabelais de Tours, France.|IFCE, Nouzilly, France.
authors.forename: Peggy
authors.initials: P
authors.lastname: Jarrier
authors.affiliation: INRA, UMR85 Physiologie de la Reproduction et des Comportements, Nouzilly, France.|CNRS, UMR6175 Physiologie de la Reproduction et des Comportements, Nouzilly, France.|Université François Rabelais de Tours, France.|IFCE, Nouzilly, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Fouchécourt
authors.affiliation: Laboratoire de Développement des Gonades, INSERM U967, CEA/DSV/iRCM/SCSR/LDG, Univ Paris Diderot, Sorbonne Paris Cité, Fontenay-Aux-Roses, France.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Duquenne
authors.affiliation: Developmental Neuroendocrinology Unit, GIGA Neurosciences, University of Liège, CHU Sart Tilman, Belgium.
authors.forename: Anne-Simone
authors.initials: AS
authors.lastname: Parent
authors.affiliation: Laboratory for Molecular Cancer Biology, Center for Human Genetics, KULeuven, Leuven, Belgium.|Center for the Biology of Disease, VIB, Leuven, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
authors.affiliation: INRA, UMR85 Physiologie de la Reproduction et des Comportements, Nouzilly, France.|CNRS, UMR6175 Physiologie de la Reproduction et des Comportements, Nouzilly, France.|Université François Rabelais de Tours, France.|IFCE, Nouzilly, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Monget
mesh_terms: D000818:Animals; D054304:Anti-Mullerian Hormone / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone; D007247:Infertility, Female / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009865:Oocytes / Q000378:metabolism / Q000473:pathology; D006080:Ovarian Follicle / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D054304:Anti-Mullerian Hormone; D005640:Follicle Stimulating Hormone; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Mdm2; female fertility; oocyte; ovary; p53