State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
Nature. 2024 Nov;635(8040):960-968. doi: 10.1038/s41586-024-08104-6. Epub 2024 Oct 30.
The dosage of X-linked genes is accurately regulated with the development of fetal germ cells (FGCs). How aberrant dosage of X-linked genes impairs FGC development in humans remains poorly understood. FGCs of patients with Klinefelter syndrome (KS), who have an extra X chromosome, provide natural models for addressing this issue. Here we demonstrate that most human FGCs in KS are arrested at an early stage, characterized by the upregulation of genes related to pluripotency, the WNT pathway and the TGF-β pathway, along with the downregulation of genes involved in FGC differentiation. The limited KS FGCs that are capable of reaching the late stage remain relatively naive. X chromosomes are not inactivated and the dosage of X-linked genes is excessive in KS FGCs. X-linked genes dominate the differentially expressed genes and are enriched in critical biological processes associated with the developmental delay of KS FGCs. Moreover, aberrant interactions between Sertoli cells and FGCs disrupt the migration of late FGCs to the basement membrane in KS. Notably, inhibition of the TGF-β pathway improves the differentiation of KS FGCs. Our findings elucidate how the extra X chromosome impairs the development of male FGCs and reveal the initial molecular events preceding germ cell loss in KS.
X 连锁基因的剂量在胎儿生殖细胞 (FGC) 的发育过程中被精确调控。X 连锁基因剂量异常如何损害人类 FGC 的发育尚不清楚。患有克氏综合征 (KS) 的患者的 FGC 提供了额外的 X 染色体，为解决这一问题提供了自然模型。在这里，我们证明大多数 KS 中的人类 FGC 都在早期停滞，其特征是与多能性、WNT 途径和 TGF-β途径相关的基因上调，同时与 FGC 分化相关的基因下调。能够达到晚期的有限 KS FGC 仍然相对幼稚。X 染色体没有失活，KS FGC 中的 X 连锁基因剂量过多。X 连锁基因主导差异表达基因，并富集与 KS FGC 发育迟缓相关的关键生物学过程。此外，支持细胞和 FGC 之间的异常相互作用破坏了 KS 中晚期 FGC 向基底膜的迁移。值得注意的是，抑制 TGF-β 途径可改善 KS FGC 的分化。我们的研究结果阐明了额外的 X 染色体如何损害男性 FGC 的发育，并揭示了 KS 中生殖细胞丢失之前的初始分子事件。
