Evolutionary Relaxation and Functional Change of INSL3 and RXFP2 May Underlie Natural Cryptorchidism in Mammals

ABSTRACT: Cryptorchidism is a common congenital abnormality that increases infertility and testicular cancer risk in adulthood. However, a few mammals exhibit naturally undescended testes while maintaining normal reproduction. The mechanisms underlying this natural cryptorchidism remain unclear. Here, we found evolutionary relaxation in INSL3 and RXFP2 of cryptorchid mammals, with the highest dN/dS ratio observed in cetaceans. Cellular experiments demonstrated that cetacean INSL3 downregulated the cAMP-PKA-CREB pathway, thereby reducing gubernacular cell proliferation and contraction. Cetacean INSL3 knock-in mice exhibited groin-located testes, nearly perfectly mimicking cryptorchid phenotypes in cetaceans and other mammals with incompletely descended testes. Collagen and muscle fibers in the gubern

SUBMITTER: Yu Zheng 

PROVIDER: S-SCDT-10_1038-S44319-025-00636-W | biostudies-other |

REPOSITORIES: biostudies-other