CARF promotes spermatogonial self-renewal and proliferation through Wnt signaling pathway.
CARF promotes spermatogonial self-renewal and proliferation through Wnt signaling pathway.
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CARF通过Wnt信号通路促进精原细胞自我更新和增殖
DOI：
10.1038/s41421-020-00212-7
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发表时间：
2020-11-17
期刊：
影响因子：
33.5
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Cui W;He X;Zhai X;Zhang H;Zhang Y;Jin F;Song X;Wu D;Shi Q;Li L
ARF的合作者（CARF）通过p53依赖性和非依赖性机制调节细胞增殖命运。最近，我们报道了CARF作为Wnt信号传导的正调节剂的新功能。尽管有这些发现，CARF的生理功能还没有得到很好的研究。在这里，我们产生了CARF敲除小鼠，发现雄性CARF−/−小鼠表现出显着受损的生育能力和支持细胞（SCO）综合征表型。进一步的研究表明，CARF在Sertoli细胞中的缺失导致GDNF表达减少，这阻碍了精原干细胞（SSCs）的自我更新。未分化精原细胞CARF的缺失会影响其增殖。这两种机制共同导致了SCO综合征表型，这可以通过Wnt信号的药理学或遗传学再激活来功能性地拯救。最后，我们确定CARFS 351 F为SCO患者的潜在致病突变。总之，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。
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 CARFS351F 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.
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