Barka Iris, Dujardin Emilie, Dewaele Aurélie, André Marjolaine, Frambourg Anne, Thépot Dominique, Jouneau Luc, Le Danvic Chrystelle, Jolivet Geneviève, Pannetier Maëlle, Mandon-Pépin Béatrice, Pailhoux Eric
Université Paris-Saclay, UVSQ, INRAE, BREED, Jouy-en-Josas, France.
École Nationale Vétérinaire d'Alfort, BREED, Maisons-Alfort, France.
Biol Reprod. 2025 Aug 13;113(2):450-465. doi: 10.1093/biolre/ioaf064.
DMRT1 is a key factor in testis development, where it is involved in sex determination and fertility. Mutations in DMRT1 have been described in humans, with patients presenting 46,XY Disorders of Sex Development (46,XY DSD) or infertility. In a previous study, we demonstrated that DMRT1 is a testis-determining factor in rabbits, with DMRT1-/- rabbits exhibiting a male to female XY sex reversal. In this study, we show that DMRT1 haploinsufficiency induces secondary infertility, with XY rabbits presenting oligospermia or even azoospermia at 2 years of age. We observed that sperm concentration decreases and sperm anomalies increase in DMRT1+/- rabbits at adulthood. Furthermore, spermatogenesis is impacted as early as 4 months (the earliest stage where spermatozoa are detected), with dysregulation of genes involved in spermatid maturation and oocyte/spermatozoa fusion, as well as overexpression of genes involved in the mitosis/meiosis transition of spermatogonial stem cells. Finally, DMRT1 haploinsufficiency impacts the earliest stages of germ cell differentiation, with persistent proliferation and pluripotency in the postnatal period. In conclusion, our findings underscore DMRT1 as a crucial factor at various stages of testicular development and reinforce its role in the multiple phenotypes observed in humans.
DMRT1是睾丸发育的关键因素，它参与性别决定和生育能力。人类中已发现DMRT1的突变，患者表现为46,XY性发育障碍（46,XY DSD）或不育。在先前的研究中，我们证明DMRT1是兔子的睾丸决定因子，DMRT1基因敲除的兔子表现出从雄性到雌性的XY性反转。在本研究中，我们表明DMRT1单倍剂量不足会导致继发性不育，XY兔子在2岁时出现少精子症甚至无精子症。我们观察到成年期DMRT1基因杂合子兔子的精子浓度降低，精子异常增加。此外，早在4个月大（检测到精子的最早阶段）精子发生就受到影响，涉及精子细胞成熟和卵母细胞/精子融合的基因失调，以及精原干细胞有丝分裂/减数分裂转变相关基因的过表达。最后，DMRT1单倍剂量不足影响生殖细胞分化的最早阶段，导致出生后生殖细胞持续增殖和多能性。总之，我们的研究结果强调了DMRT1在睾丸发育各个阶段的关键作用，并强化了其在人类观察到的多种表型中的作用。
