Pin1 regulates the timing of mammalian primordial germ cell proliferation

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Abstract
Primordial germ cells (PGCs) give rise to male and female germ cells to transmit the genome from generation to generation. Defects in PGC development often result in infertility. In the mouse embryo, PGCs undergo proliferation and expansion during and after their migration to the gonads from 8.5 to 13.5 days post coitum (dpc). We show that a peptidyl-prolyl isomerase, Pin1, is involved in the regulation of mammalian PGC proliferation. We discovered that both the male and female Pin1-/- mice had profound fertility defects. Investigation of the reproductive organs revealed significantly fewer germ cells in the adult Pin1-/- testes and ovaries than in wild type or heterozygotes, which resulted from Pin1-/- males and females being born with severely reduced number of gonocytes and oocytes. Further studies in 8.5 to 13.5 dpc Pin1-/- embryos showed that PGCs were allocated properly at the base of the allantois, but their cell expansion was progressively impaired, resulting in a markedly reduced number of PGCs at 13.5 dpc. Analyses using markers of cell cycle parameters and apoptosis revealed that Pin1-/- PGCs did not undergo cell cycle arrest or apoptosis. Instead, Pin1-/- PGCs had a lower BrdU labeling index compared with wild-type PGCs. We conclude that PGCs have a prolonged cell cycle in the absence of Pin1, which translates into fewer cell divisions and strikingly fewer Pin1-/- PGCs by the end of the proliferative phase. These results indicate that Pin1 regulates the timing of PGC proliferation during mouse embryonic development.