The DNA damage response is required for oocyte cyst breakdown and follicle formation in mice.
| Title: | The DNA damage response is required for oocyte cyst breakdown and follicle formation in mice. |
|---|---|
| Authors: | Martínez-Marchal A; Unitat de Citologia i Histologia, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.; Grup d'Inestabilitat i Integritat del genoma, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.; Huang Y; Unitat de Citologia i Histologia, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.; Grup d'Inestabilitat i Integritat del genoma, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.; Guillot-Ferriols MT; Unitat de Citologia i Histologia, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.; Grup d'Inestabilitat i Integritat del genoma, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.; Ferrer-Roda M; Unitat de Citologia i Histologia, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.; Grup d'Inestabilitat i Integritat del genoma, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.; Guixé A; Unitat de Citologia i Histologia, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.; Grup d'Inestabilitat i Integritat del genoma, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.; Garcia-Caldés M; Grup d'Inestabilitat i Integritat del genoma, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.; Unitat de Biologia Cel·lular i Genètica Mèdica, Facultat de Medicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.; Roig I; Unitat de Citologia i Histologia, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.; Grup d'Inestabilitat i Integritat del genoma, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain. |
| Source: | PLoS genetics [PLoS Genet] 2020 Nov 18; Vol. 16 (11), pp. e1009067. Date of Electronic Publication: 2020 Nov 18 (Print Publication: 2020). |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: San Francisco, CA : Public Library of Science, c2005- |
| MeSH Terms: | DNA Damage/*genetics ; Oogonia/*metabolism ; Ovarian Follicle/*metabolism; Apoptosis/physiology ; Cell Cycle Proteins/genetics ; Checkpoint Kinase 2/genetics ; Checkpoint Kinase 2/metabolism ; Cysts/metabolism ; DNA Damage/physiology ; Endodeoxyribonucleases/genetics ; Endodeoxyribonucleases/metabolism ; Meiosis/physiology ; Meiotic Prophase I/physiology ; Oocytes/metabolism ; Oocytes/physiology ; Oogonia/physiology ; Ovarian Follicle/physiology ; Ovary/metabolism ; Progesterone/metabolism ; Animals ; Female ; Mice ; Mice, Inbred C57BL ; Meiotic Recombination Protein SPO11 |
| Abstract: | 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. |
| Competing Interests: | The authors have declared that no competing interests exist. |
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| Substance Nomenclature: | 0 (Cell Cycle Proteins); EC 2.7.1.11 (Checkpoint Kinase 2); EC 3.1.- (Endodeoxyribonucleases); 4G7DS2Q64Y (Progesterone); 0 (Meiotic Recombination Protein SPO11); EC 2.7.11.1 (Chek2 protein, mouse) |
| Entry Date(s): | Date Created: 20201118 Date Completed: 20210201 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC7710113 |
| DOI: | 10.1371/journal.pgen.1009067 |
| PMID: | 33206637 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't