NEK2 Contributes to the Protection Against Cryptorchidism Outcomes

Cryptorchidism, characterized by the failure of testicular descent, is a common congenital disorder adversely affecting male reproductive health. Intriguingly, the NIMA-related kinase 2 (NEK2) gene has been implicated in various cellular processes, but its role in cryptorchidism remains underexplored.

To elucidate NEK2's role, the researchers utilized NEK2 knockout mice, analyzing testes histology with hematoxylin-eosin (HE) staining and assessing sperm morphology by Diff-Quick staining. Immunohistofluorescence evaluated Leydig cell count, while Western blotting and immunohistochemistry analyzed 3β-hydroxysteroid dehydrogenase 1 (HSD3B1), critical for testosterone synthesis. Mouse testosterone levels were quantified by ELISA, and RT-qPCR examined testicular Wnt-β-catenin and HIPPO pathway expression.

NEK2-deficient mice exhibited significantly increased cryptorchidism incidence, decreased Leydig cell number, reduced testis/body weights, and elevated sperm malformations. Histological analysis revealed pronounced testicular damage. Western blotting and immunohistochemistry showed unchanged nuclear receptor subfamily 5 (NR5A1) and insulin-like protein 3 (INSL3), but decreased HSD3B1 in NEK2^-/- mice, leading to lower testosterone levels. Mechanistically, NEK2 knockout suppressed wingless/integrated (Wnt)-β-catenin and activated HIPPO, causing mammalian sterile 20-like protein kinase 2 (MST2)-large tumor suppressor homolog 2 (LATS2)-mediated downregulation of yes-associated protein (YAP).

These findings highlight NEK2's essential role in regulating testicular descent and spermatogenesis, implicating it as a potential target for cryptorchidism.