ATR function is indispensable to allow proper mammalian follicle development
Mammalian female fertility relies on the proper development of follicles. Right after birth in the mouse, oocytes associate with somatic ovarian cells to form follicles. These follicles grow during the adult lifetime to produce viable gametes. In this study, we analyzed the role of the ATM and rad3-related (ATR) kinase in mouse oogenesis and folliculogenesis using a hypomorphic mutation of the Atr gene (Murga et al. 2009). Female mice homozygotes for this allele have been reported to be sterile. Our data show that female meiotic prophase is not grossly altered when ATR levels are reduced. However, follicle development is substantially compromised, since Atr mutant ovaries present a decrease of growing follicles. Comprehensive analysis of follicular cell death and proliferation suggest that wild-type levels of ATR are required to achieve optimal follicular development. Altogether, these findings suggest that reduced ATR expression causes sterility due to defects in follicular progression rather than in meiotic recombination. We discuss the implications of these findings for the use of ATR inhibitors such as anti-cancer drugs and its possible side-effects on female fertility.
KeywordsFolliculogenesis ATR Oogenesis Replication Apoptosis
We wish to thank O. Fernández-Capetillo (CNIO, Spain) for providing us with the Seckel allele.
This work was supported by the Ministerio de Ciencia e Innovación (BFU2010-18965, BFU2013-43965-P and BFU2016-80370-P, IR) and by the UAB-Aposta award to young investigators (APOSTA2011-03, IR).
Compliance with ethical standards
Experimental procedures performed in the present work conform to protocol CEEAAH 1091 (DAAM6395) approved by the Ethics Committee for Animal Experimentation of the Universitat Autònoma de Barcelona and the Catalan Government.
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