Y Chromosome Genes Play Roles in Sex-Dependent Development Outside of Sex Determination

Despite the small number of Y chromosome genes, their ad-equate expression is required for regulation of transcription, translation, and protein stability of male individuals beyond sex-determination. In addition to their roles in male infertility, Y chromosome has an inevitable role in the sexual dimorphism of healthy and disease phenotypes and development. We previ-ously reported that the Y chromosome genes, DDX3Y, is as-sociated to neural induction in human embryonal carcinoma NTERA-2 cell line. Furthermore, TBL1Y may play an impor-tant role in cardiac development. We recently observed that another Y chromosome gene, KDM5D, may also contribute in cardiac differentiation of human embryonic stem cells (hESCs). We also found that most of the Y chromosome genes like SRY showed high expression level in primed versus naïve hESCs. Therefore, we hypothesize that SRY prevents WNT/β-catenin signaling by interaction and inhibition of β-catenin transloca-tion. By the loss of function approach through depletion of SRY of the primed cells, we observed that the expression of pluri-potency markers and WNT signaling target genes such as Bra-chuary, GCBM, TBX2 and TBX3 increased in si-SRY treated cells. In conclusion, we revealed that inhibition of SRY results in nucleus translocation of β-catenin and up-regulation of WNT signaling pathway which important to naïve conversion. Our findings present a potential role for the contribution of Y chro-mosome genes in sex-dependent development outside of sex determination.