Apoptosis of Sertoli cells after conditional ablation of murine double minute 2 (Mdm2) gene is p53-dependent and results in male sterility
2016
Fouchécourt, Sophie | Livera, G. | Messiaen, S. | Fumel, Betty | Parent, A.S. | Marine, J.C. | Monget, Philippe | Physiologie de la reproduction et des comportements [Nouzilly] (PRC) ; Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS) | Université Paris Diderot - Paris 7 (UPD7) | PRES Sorbonne Paris Cité | U 967 ; Institut National de la Santé et de la Recherche Médicale (INSERM) | Developmental Neuroendocrinology Unit, GIGA Neurosciences ; Université de Liège = University of Liège = Universiteit van Luik = Universität Lüttich (ULiège) | Laboratory for Molecular Cancer Biology, Center for Human Genetics ; Université Catholique de Louvain = Catholic University of Louvain (UCL) | Flanders Institute for Biotechnology | Agence Nationale pour la Recherche ('Biodiversité, évolution des écosystemes, écosystemes productifs, agronomie' grant; 2011-2013):TimeOfLife2 and EarlyFoll
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.
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