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

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

Nature, 2024, vol. 635, issue 8040, 960-968

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-08104-6

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