title: Apoptosis of Sertoli cells after conditional ablation of murine double minute 2 (Mdm2) gene is p53-dependent and results in male sterility.
abstract: Beside its well-documented role in carcinogenesis, the function of p53 family has been more recently revealed in development and female reproduction, but it is still poorly documented in male reproduction. We specifically tested this possibility by ablating Mdm2, an E3 ligase that regulates p53 protein stability and transactivation function, specifically in Sertoli cells (SCs) using the AMH-Cre line and created the new SC-Mdm2(-/-) line. Heterozygous SC-Mdm2(-/+) adult males were fertile, but SC-Mdm2(-/-) males were infertile and exhibited: a shorter ano-genital distance, an extra duct along the vas deferens that presents a uterus-like morphology, degenerated testes with no organized seminiferous tubules and a complete loss of differentiated germ cells. In adults, testosterone levels as well as StAR, P450c17 (Cyp17a1) and P450scc (Cyp11a1) mRNA levels decreased significantly, and both plasma LH and FSH levels increased. A detailed investigation of testicular development indicated that the phenotype arose during fetal life, with SC-Mdm2(-/-) testes being much smaller at birth. Interestingly, Leydig cells remained present until adulthood and fetal germ cells abnormally initiated meiosis. Inactivation of Mdm2 in SCs triggered p53 activation and apoptosis as early as 15.5 days post conception with significant increase in apoptotic SCs. Importantly, testis development occurred normally in SC-Mdm2(-/-) lacking p53 mice (SC-Mdm2(-/-)p53(-/-)) and accordingly, these mice were fertile indicating that the aforementioned phenotypes are entirely p53-dependent. These data not only highlight the importance of keeping p53 in check for proper testicular development and male fertility but also certify the critical role of SCs in the maintenance of meiotic repression.
authors.affiliation: INRA, UMR85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France.|CNRS, UMR6175 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France.|Université François Rabelais de Tours, F-37041 Tours, France.|IFCE, F-37380 Nouzilly, France.
authors.forename: S
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, F-92265 Fontenay-Aux-Roses, France.
authors.forename: G
authors.initials: G
authors.lastname: Livera
authors.affiliation: Laboratoire de Développement des Gonades, INSERM U967, CEA/DSV/iRCM/SCSR/LDG, Univ Paris Diderot, Sorbonne Paris Cité, F-92265 Fontenay-Aux-Roses, France.
authors.forename: S
authors.initials: S
authors.lastname: Messiaen
authors.affiliation: INRA, UMR85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France.|CNRS, UMR6175 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France.|Université François Rabelais de Tours, F-37041 Tours, France.|IFCE, F-37380 Nouzilly, France.
authors.forename: B
authors.initials: B
authors.lastname: Fumel
authors.affiliation: Developmental Neuroendocrinology Unit, GIGA Neurosciences, University of Liège, CHU Sart Tilman, Liège, Belgium.
authors.forename: A-S
authors.initials: AS
authors.lastname: Parent
authors.affiliation: Laboratory for Molecular Cancer Biology, Center for Human Genetics, KU Leuven, Leuven, Belgium.|Center for the Biology of Disease, VIB, Leuven, Belgium.
authors.forename: J-C
authors.initials: JC
authors.lastname: Marine
authors.affiliation: INRA, UMR85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France.|CNRS, UMR6175 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France.|Université François Rabelais de Tours, F-37041 Tours, France.|IFCE, F-37380 Nouzilly, France.
authors.forename: P
authors.initials: P
authors.lastname: Monget
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D055786:Gene Knockout Techniques; D007248:Infertility, Male / Q000097:blood / Q000235:genetics*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012671:Seminiferous Tubules / Q000378:metabolism / Q000473:pathology; D012708:Sertoli Cells / Q000502:physiology*; D013739:Testosterone / Q000097:blood; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; C415788:Mtbp protein, mouse; D016159:Tumor Suppressor Protein p53; D013739:Testosterone; D007986:Luteinizing Hormone