SCIENCE@home

Evolutionary relaxation and functional change of INSL3 and RXFP2 may underlie natural cryptorchidism in mammals

Yu Zheng,Simin Chai,Cuijuan Zhong,Yixuan Sun,Shixia Xu,Wenhua Ren,Guang Yang

Published 2025 in EMBO Reports

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 gubernaculum of transgenic mice were reduced, with differentially expressed genes enriched in muscle development and contraction pathways. Additionally, the knock-in mice displayed male sterility, impaired testicular development, and upregulated inflammatory pathways in the testes. Our findings reveal how evolutionary changes in the INSL3/RXFP2 pathway contribute to natural cryptorchidism in mammals and provide insights for investigating reproductive health and cancer resistance in cryptorchid species. This study examines how evolutionary relaxation and functional change of INSL3 and RXFP2 relate to natural cryptorchidism in mammals. Functional assays and interspecies knock-in mice indicate partial INSL3 activity with downstream developmental and reproductive consequences. Comparative analyses identifies relaxed selection on INSL3 and RXFP2 in naturally cryptorchid mammals. Cetacean INSL3 knock-in mice display cryptorchid phenotypes and reduced fertility. Transcriptomic profiling reveals disruptions in developmental and spermatogenic pathways. Functional assays and in vivo models indicate partial INSL3 activity associated with reproductive phenotypes. Comparative analyses identifies relaxed selection on INSL3 and RXFP2 in naturally cryptorchid mammals. Cetacean INSL3 knock-in mice display cryptorchid phenotypes and reduced fertility. Transcriptomic profiling reveals disruptions in developmental and spermatogenic pathways. Functional assays and in vivo models indicate partial INSL3 activity associated with reproductive phenotypes. This study examines how evolutionary relaxation and functional change of INSL3 and RXFP2 relate to natural cryptorchidism in mammals. Functional assays and interspecies knock-in mice indicate partial INSL3 activity with downstream developmental and reproductive consequences.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-56 of 56 references · Page 1 of 1

CITED BY

  • No citing papers are available for this paper.

Showing 0-0 of 0 citing papers · Page 1 of 1