Abstract
Rad54 is an important factor in the homologous recombination pathway of DNA double-strand break repair. However, Rad54 knockout (KO) mice do not exhibit overt phenotypes at adulthood, even when exposed to radiation. In this study, we show that in Rad54 KO mouse the germline is actually altered. Compared with the wild-type (WT) animals, these mice have less premeiotic germ cells. This germ cell loss is found as early as in E11.5 embryos, suggesting an early failure during mutant primordial germ cells development. Both testicular and ovarian KO germ cells exhibited high radiation sensitivity leading to a long-term gametogenesis defect at adulthood. The KO female germline was particularly affected displaying decreased litter size or sterility. Spermatogenesis recovery after irradiation was slower and incomplete in Rad54 KO mice compared with that of WT mice, suggesting that loss of germ stem cell precursors is not fully compensated along the successive rounds of spermatogenesis. Finally, spermatogenesis recovery after postnatal irradiation is in part regulated by glial-cell-line-derived neurotrophic factor (GDNF) in KO but not in irradiated WT mice, suggesting that Sertoli cell GDNF production is stimulated upon substantial germ cell loss only. Our findings suggest that Rad54 has a key function in maintaining genomic integrity of the developing germ cells.
Highlights
Female germ cells enter meiosis at E13.5 and arrest in diplotene stage at birth
Primordial germ cells (PGC) first appear at embryonic day (E) 7.0, in the extra-embryonic mesoderm at the base of the allantois. They migrate into the hindgut endoderm at E8.0 and travel along the dorsal mesentery by E9.5 to start the colonization of the genital ridges at E10.5-E11.5.1,2 Commitment of germ cells to male or female development occurs by E12.5
Murine male germ cells undergo a period of quiescence from E13.5 to birth and differentiate into spermatogonial populations including a pool of cells with spermatogonial progenitor cell properties.[3]
Summary
Female germ cells enter meiosis at E13.5 and arrest in diplotene stage at birth. Murine male germ cells undergo a period of quiescence from E13.5 to birth and differentiate into spermatogonial populations including a pool of cells with spermatogonial progenitor cell properties.[3] By 8 to 10 days after birth meiosis is initiated and the first spermatozoa appear 35 days after birth (P35). Non homologous end joining, which consists of the simple ligation of DNA strands, is the fastest mechanism and is functional in all phases of the cell cycle.[10] Homologous recombination (HR) is functional only in S and G2 phases as a homologous DNA template is needed, usually the sister chromatid This is the reason why HR is considered as the most reliable pathway to achieve high fidelity cellular DNA repair.[11]
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