北京大学乔杰等研究人员合作揭示额外的X染色体如何损害男性胎儿生殖细胞的发展。相关论文于2024年10月30日在线发表在《自然》杂志上。

研究人员表示，X连锁基因的剂量在胎儿生殖细胞（FGC）发育过程中被精确调控。额外的X染色体如何影响人类FGC的发展尚不清楚。患有克莱因费尔特综合症（KS）的患者FGC，由于其多了一条X染色体，成为研究这一问题的自然模型。

研究人员发现大多数KS患者的FGC在早期阶段停滞，表现为与多能性、WNT途径和TGF-β途径相关的基因上调，同时FGC分化相关基因下调。只有少数KS FGC能够达到晚期阶段，且仍然相对初始。KS FGC中的X染色体未被失活，进而X连锁基因的剂量过多。X连锁基因在差异表达基因中占主导地位，并且富集于与KS FGC发育延迟相关的关键生物过程。

此外，Sertoli细胞与FGC之间的异常相互作用干扰了KS中晚期FGC向基膜的迁移。值得注意的是，抑制TGF-β途径改善了KS FGC的分化。该研究阐明了额外的X染色体如何损害男性FGC的发展，并揭示了KS中生殖细胞丧失前的初步分子事件。

附：英文原文

Title: How the extra X chromosome impairs the development of male fetal germ cells

Author: Lu, Yongjie, Qin, Meng, He, Qilong, Hua, Lingyue, Qi, Xintong, Yang, Ming, Guo, Qianying, Liu, Xixi, Zhang, Zhe, Xu, Fanqing, Ding, Ling, Wu, Yixuan, Zhang, Cong, Zhai, Fan, Liu, Qiang, Li, Jiaxin, Yuan, Pengbo, Shi, Xiaoming, Wang, Xueju, Zhao, Cheng, Lian, Ying, Li, Rong, Wei, Yuan, Yan, Liying, Yuan, Peng, Qiao, Jie

Issue&Volume: 2024-10-30

Abstract: The dosage of X-linked genes is accurately regulated with the development of fetal germ cells (FGCs)1,2. 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 issue3. 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.

DOI: 10.1038/s41586-024-08104-6

Source: https://www.nature.com/articles/s41586-024-08104-6