Deficiency of NR2C2 accelerates senescence of testicular Leydig cells and infertility in male mice

The Leydig cell is one of the components that make up the testicular microenvironment, playing a crucial role in male reproductive function by secreting androgens and cytokines. The present study found that knocking down NR2C2, a member of the 2C group of the nuclear receptor family, can lead to senescent phenotype in mouse primary Leydig cells, with increased cell apoptosis and DNA damage, enhanced SA-β-Gal activity, and decreased glutathione levels. The fertility of Nr2c2 heterozygous knockout mice (Nr2c2+/-) is impaired. The testosterone levels of Nr2c2+/- mice at 12 months of age were lower than those of wild-type littermates of the same age, accompanied by increased expression of P21 protein in testicular tissue. Mechanistically, NR2C2 promotes transcription of target genes such as Akt2 and Qsox2 by binding to DR elements on their promoters. In addition, NR2C2 participates in regulating alternative splicing of target mRNAs (Rnf111, Cdkn2c, Igf1r and Fnip2) at the post transcriptional level by interacting with hnRNPH1 or other splicing factors. Our study for the first time reveals that NR2C2 is a core regulatory factor in resisting aging in testicular Leydig cells. It provides a novel potential target for male infertility and reproductive aging-related disorders.