Undescended testis (UDT), or cryptorchidism, is one of the most common male congenital abnormalities, affecting 6% of male births. As well as hormonal inputs, testicular development is also regulated by Wnt signalling; loss of Wnt4 in male embryos results in delayed testicular development and consequently impacts male fertility. How Wnt4 regulates this process, however, is unclear. In this study, Carolina Jorgez and colleagues investigate this role of Wnt4 by generating a mouse line with a conditional knockout of Wnt4 specifically in the gubernaculum (the structure connecting the testis to the abdominal wall). The authors find that loss of Wnt4 in the gubernaculum causes unilateral UDT of the left testicle with 100% penetrance and reduced fertility of these mice, attributed to decreases in sperm count and motility. Interestingly, although the right testicle consistently descends as in wild-type mice, it has disrupted morphology and both testes have altered expression of male and female gonadal genes. Finally, the authors conduct a study in humans and identify several WNT4 variants in boys with UDT. Together, these findings highlight Wnt4 as a crucial regulator of testicular development and demonstrates that Wnt4 should be considered in the clinical etiology of UDT.
