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^S351F 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.

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，我们生成了CARF基因敲除小鼠并发现雄性CARF ^-/-小鼠表现出显着受损的生育力和仅支持细胞 (SCO) 综合征表型。进一步的研究表明，支持细胞中 CARF 的缺失导致 GDNF 表达降低，从而阻碍了精原干细胞 (SSC) 的自我更新。同时，未分化精原细胞中的 CARF 损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，这可以通过 Wnt 信号的药理学或遗传重新激活在功能上挽救。最后，我们将 CARF ^S351F鉴定为 SCO 患者的潜在致病突变。总的来说，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。