Maximizing the ovarian reserve in mice by evading LINE-1 genotoxicity
| Autor: | Alex Bortvin, Safia Malki, Marla E. Tharp |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male DNA damage Science Mutant General Physics and Astronomy Retrotransposon Apoptosis Biology Oogenesis General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Mice 0302 clinical medicine Fetus medicine Transposition Animals Ovarian reserve Ovarian Reserve lcsh:Science Mice Knockout Multidisciplinary Mutagenicity Tests RNA-Binding Proteins General Chemistry G2-M DNA damage checkpoint Oocyte Cell biology Mice Inbred C57BL Checkpoint Kinase 2 030104 developmental biology medicine.anatomical_structure Fertility Long Interspersed Nucleotide Elements Argonaute Proteins Oocytes Female lcsh:Q 030217 neurology & neurosurgery DNA Damage |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-13 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-14055-8 |
| Popis: | Female reproductive success critically depends on the size and quality of a finite ovarian reserve. Paradoxically, mammals eliminate up to 80% of the initial oocyte pool through the enigmatic process of fetal oocyte attrition (FOA). Here, we interrogate the striking correlation of FOA with retrotransposon LINE-1 (L1) expression in mice to understand how L1 activity influences FOA and its biological relevance. We report that L1 activity triggers FOA through DNA damage-driven apoptosis and the complement system of immunity. We demonstrate this by combined inhibition of L1 reverse transcriptase activity and the Chk2-dependent DNA damage checkpoint to prevent FOA. Remarkably, reverse transcriptase inhibitor AZT-treated Chk2 mutant oocytes that evade FOA initially accumulate, but subsequently resolve, L1-instigated genotoxic threats independent of piRNAs and differentiate, resulting in an increased functional ovarian reserve. We conclude that FOA serves as quality control for oocyte genome integrity, and is not obligatory for oogenesis nor fertility. Mammals lose up to 80% of their finite oocyte supply during fetal development. Here the authors interrogate mechanisms of fetal oocyte attrition in mice, driven by the simultaneous upregulation of LINE-1 retrotransposon activity and inhibit these mechanisms to increase the functional ovarian reserve. |
| Databáze: | OpenAIRE |
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