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ATR function is indispensable to allow proper mammalian follicle development

  • Sarai Pacheco
  • Andros Maldonado-Linares
  • Montserrat Garcia-Caldés
  • Ignasi RoigEmail author
Original Article


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.


Folliculogenesis ATR Oogenesis Replication Apoptosis 



We wish to thank O. Fernández-Capetillo (CNIO, Spain) for providing us with the Seckel allele.

Funding information

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.

Supplementary material

412_2019_723_MOESM1_ESM.docx (32 kb)
Supplementary Table 1 (DOCX 31 kb)
412_2019_723_MOESM2_ESM.pdf (605 kb)
Supplementary figure 1 Follicle number per section is affected in adult Seckel mouse ovaries. Quantification of the number of follicles present at different stages in eight alternate ovarian sections from two ovaries of the indicated age and genotype. p values are from the t test. (PDF 604 kb)
412_2019_723_MOESM3_ESM.pdf (749 kb)
Supplementary figure 2 Seckel mouse oocytes occupy a larger area of the follicle than do control ones. (a) Indirect analysis of the number of follicular cells surrounding an oocyte. Each point represents the measure of the relative area occupied by an oocyte (blue circumference in the example image inset) in a particular follicle (green circumference) for the indicated genotypes at different stages of folliculogenesis. Horizontal black lines in the graph denote the means. Primary and small secondary follicles from Seckel ovaries present larger relative oocyte areas than do control follicles, suggesting a reduction in the number of granulosa cells surrounding those oocytes. (b) Quantification of the size of control and Seckel mouse oocyte along folliculogenesis. Horizontal line denotes the means. (PDF 748 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Genome Integrity and Instability Group, Institut de Biotecnologia i BiomedicinaUniversitat Autònoma de BarcelonaCerdanyola del VallèsSpain
  2. 2.Department of Cell Biology, Physiology and ImmunologyUniversitat Autònoma de BarcelonaCerdanyola del VallèsSpain
  3. 3.MRC Clinical Sciences Centre, Faculty of MedicineImperial College LondonLondonUK

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