The DNA damage response is required for oocyte cyst breakdown and follicle formation in mice
Autoři:
Ana Martínez-Marchal aff001; Yan Huang aff001; Maria Teresa Guillot-Ferriols aff001; Mònica Ferrer-Roda aff001; Anna Guixé aff001; Montserrat Garcia-Caldés aff002; Ignasi Roig aff001
Působiště autorů:
Unitat de Citologia i Histologia, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
aff001; Grup d’Inestabilitat i Integritat del genoma, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
aff002; Unitat de Biologia Cel·lular i Genètica Mèdica, Facultat de Medicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
aff003
Vyšlo v časopise:
The DNA damage response is required for oocyte cyst breakdown and follicle formation in mice. PLoS Genet 16(11): e1009067. doi:10.1371/journal.pgen.1009067
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009067
Souhrn
Mammalian oogonia proliferate without completing cytokinesis, forming cysts. Within these, oocytes differentiate and initiate meiosis, promoting double-strand break (DSBs) formation, which are repaired by homologous recombination (HR) causing the pairing and synapsis of the homologs. Errors in these processes activate checkpoint mechanisms, leading to apoptosis. At the end of prophase I, in contrast with what is observed in spermatocytes, oocytes accumulate unrepaired DSBs. Simultaneously to the cyst breakdown, there is a massive oocyte death, which has been proposed to be necessary to enable the individualization of the oocytes to form follicles. Based upon all the above-mentioned information, we hypothesize that the apparently inefficient HR occurring in the oocytes may be a requirement to first eliminate most of the oocytes and enable cyst breakdown and follicle formation. To test this idea, we compared perinatal ovaries from control and mutant mice for the effector kinase of the DNA Damage Response (DDR), CHK2. We found that CHK2 is required to eliminate ~50% of the fetal oocyte population. Nevertheless, the number of oocytes and follicles found in Chk2-mutant ovaries three days after birth was equivalent to that of the controls. These data revealed the existence of another mechanism capable of eliminating oocytes. In vitro inhibition of CHK1 rescued the oocyte number in Chk2-/- mice, implying that CHK1 regulates postnatal oocyte death. Moreover, we found that CHK1 and CHK2 functions are required for the timely breakdown of the cyst and to form follicles. Thus, we uncovered a novel CHK1 function in regulating the oocyte population in mice. Based upon these data, we propose that the CHK1- and CHK2-dependent DDR controls the number of oocytes and is required to properly break down oocyte cysts and form follicles in mammals.
Klíčová slova:
Birth – DNA damage – DNA repair – Fetal development – Mammalian genomics – Meiotic prophase – Oocytes – Ovaries
Zdroje
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