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  • br Results br Discussion FXR was initially shown to regulate

    2018-10-22


    Results
    Discussion FXRα was initially shown to regulate the enterohepatic cycle and BA biosynthesis. In recent decades, many studies have demonstrated its involvement in other physiological functions (digestion, immunity) and diseases such as diabetes and cancer. FXRα participates in the homeostasis of steroids through the control of their synthesis and/or catabolism (Baptissart et al., 2013). To date, in the testis FXRα has been shown to be expressed in Leydig EMD638683 where it controls testicular testosterone metabolism. However, its effects on the exocrine function have not yet been explored. Here we identified unexpected roles of FXRα in testis physiology, mainly in the germ cell lineage.
    Experimental Procedures
    Author Contributions
    Acknowledgments This work was funded by Inserm, CNRS, Clermont Université, Ministère de l’Enseignement Supérieur et de la recherche (to M.B.), Ligue contre le Cancer (Comité Puy de Dôme to D.H.V.), Nouveau Chercheur Auvergne (no. R12087CC to D.H.V.), ANR Jeune Chercheur (no. 1103 to D.H.V.), and Plan Cancer – Cancer-Environnement InCa/Inserm (C14012CS to D.H.V.). We also thank Anipath platform from the GReD and the animal house staff (Sandrine Plantade, Philippe Mazuel, and Khirredine Ouchen).
    Introduction Primordial germ cells (PGCs) are the pioneering cells of the germline. Correct formation of PGCs is necessary for the differentiation of high-quality haploid gametes and ultimately reproductive success as adults. In the mouse, PGC precursors first develop from the epiblast at the end of gastrulation at embryonic day 6.25 (E6.25) (Kurimoto et al., 2008). Definitive PGCs are identified 24 hr later at E7.25 in an extra-embryonic structure called an allantois. At this stage PGCs express transcription factors required for pluripotency as well as germline development (Kurimoto et al., 2008). From E7.5 to E8.5, the PGCs leave their extra-embryonic location, enter the embryo, and migrate toward the genital ridges. The PGCs approach and colonize the genital ridges beginning at E10.5. By E11.5, the PGCs have finished colonizing the ridge, and the gonad is now referred to as an indifferent gonad. During the migration and colonization stages, the nascent PGCs maintain a latent pluripotency program (Hargan-Calvopina et al., 2016; Jameson et al., 2012). At E12.5, male gonads can be distinguished from female gonads by the formation of immature testis cords (Combes et al., 2009). Between E12.5 and E14.5 the male PGCs enter G0 arrest, downregulating most of the transcribed pluripotency-associated genes to become pro-spermatogonia (Western et al., 2008). During the pro-spermatogonia stage, male germ cells undergo epigenetic remodeling in preparation for differentiation into spermatogonia after birth. Given that PGCs are the founding germline cells in human reproduction, and abnormal PGC formation can lead germline loss, understanding the basic cell and molecular biology of PGCs, and creating bioassays that discriminate PGCs functionally are critical areas of investigation. Capitalizing on their knowledge of mouse PGC development (Ohinata et al., 2009; Saitou et al., 2002), Hayashi and colleagues devised methods to differentiate mouse embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) into mouse PGC-like cells (PGCLCs). Remarkably, the resulting PGCLCs could be transplanted into ovaries or testes, giving rise to fertilization competent eggs, sperm, and viable offspring (Hayashi et al., 2011, 2012). The differentiation of human PSCs (hPSCs) into PGCLCs has emerged as a major new model for uncovering the cell and molecular events in human PGC specification (Irie et al., 2015; Sasaki et al., 2015; Sugawa et al., 2015). In the long term, this approach may have implications for treating infertility. However, unlike the mouse model, an approach to prove that human PGCLCs are functional following transplantation is not currently forthcoming. Methods for PGCLC differentiation in humans are based upon similar signaling principles to the mouse, namely the use of bone morphogenetic protein 4 (BMP4) to induce PGCLC fate. However, the transcription factor network downstream of BMP4 may be different in humans (Irie et al., 2015; Sasaki et al., 2015; Sugawa et al., 2015). This suggests either divergence of the transcriptional factor network that drives PGC formation, or an artifact of in vitro differentiation. To discriminate between the two possibilities, it is necessary to investigate the molecular and functional characteristics of bona fide PGCs in higher primates so that appropriate standards can be established for the generation of PGCLCs in primate models.