Abstract
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.
Highlights
Reproduction is critical for passing genetic information between generations for all mammalian species
Inactivation of Collaborator of ARF (CARF) leads to SCO syndrome To explore the physiological function of CARF, we first examined the expression of CARF in multiple organs of mice by quantitative real-time PCR and western blot analysis
We found that CARF was highly expressed in the testis, thymus, and spleen (Supplementary, Fig. S1a, b)
Summary
Reproduction is critical for passing genetic information between generations for all mammalian species. An adult male continuously produces millions of haploid spermatozoa daily[1]. The process of spermatogenesis is under complex regulation of various regulators including external factors and internal factors[2]. Detailed regulatory mechanisms have not been well understood. Infertility affects about 10–15% of reproductive-aged couples on a global scale, with male factors being the cause in approximately half[3]. Sertoli-cell-only (SCO) syndrome is one important cause of male infertility, in which only Sertoli cells line the seminiferous tubules without any germ cells. There is no accurate data at present, it is estimated that SCO patients may account
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
