NEK2 Contributes to the Protection Against Cryptorchidism Outcomes

Background

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.

Methods

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.

Results

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).

Conclusions

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