Cui Wenhao, He Xiaoli, Zhai Xiaohong, Zhang Huan, Zhang Yuanwei, Jin Fei, Song Xiaomin, Wu Dianqing, Shi Qinghua, Li Lin
State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
School of Life Science and Technology, Shanghai Tech University, Shanghai, 201210, China.
Cell Discov. 2020 Nov 17;6(1):85. doi: 10.1038/s41421-020-00212-7.
Collaborator of ARF (CARF) regulates cell proliferative fate through both p53-dependent and -independent mechanisms. Recently, we reported a new function of CARF as a positive regulator of Wnt signaling. Despite these findings, the physiological function of CARF has not been well studied. Here, we generated CARF knockout mice and found that male CARF mice exhibited significantly impaired fertility and Sertoli-cell-only (SCO) syndrome phenotypes. Further studies revealed that loss of CARF in Sertoli cells led to decreased GDNF expression, which hindered spermatogonial stem cells (SSCs) self-renewal. Meanwhile, CARF loss in undifferentiated spermatogonia impaired their proliferation. These two mechanisms together led to SCO syndrome phenotypes, which could be functionally rescued by pharmacological or genetic reactivation of Wnt signaling. Finally, we identified CARF as a potential pathogenic mutation in an SCO patient. Overall, our findings reveal important roles of CARF in spermatogonial self-renewal and proliferation through the Wnt signaling pathway.
急性肾损伤协作因子（CARF）通过p53依赖和非依赖机制调节细胞增殖命运。最近，我们报道了CARF作为Wnt信号通路正向调节因子的新功能。尽管有这些发现，但CARF的生理功能尚未得到充分研究。在此，我们构建了CARF基因敲除小鼠，发现雄性CARF小鼠表现出明显的生育能力受损和唯支持细胞（SCO）综合征表型。进一步研究表明，支持细胞中CARF的缺失导致胶质细胞源性神经营养因子（GDNF）表达降低，从而阻碍了精原干细胞（SSCs）的自我更新。同时，未分化精原细胞中CARF的缺失损害了它们的增殖。这两种机制共同导致了SCO综合征表型，通过Wnt信号通路的药理学或基因再激活可在功能上挽救该表型。最后，我们在一名SCO患者中鉴定出CARF为潜在的致病突变。总体而言，我们的研究结果揭示了CARF通过Wnt信号通路在精原细胞自我更新和增殖中的重要作用。
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