Inactivation of JNK signalling results in polarity loss and cell senescence of Sertoli cell

Zhiming Shen; Yang Gao; Xuedong Sun; Min Chen; Changhuo Cen; Mengyue Wang; Nan Wang; Bowen Liu; Jiayi Li; Xiuhong Cui; Jian Hou; Yuhua Shi; Fei Gao

doi:10.1002/cpr.13760

Cell Proliferation ›› 2025, Vol. 58 ›› Issue (2) : e13760 DOI: 10.1002/cpr.13760

ORIGINAL ARTICLE

Inactivation of JNK signalling results in polarity loss and cell senescence of Sertoli cell

Zhiming Shen ¹^,²
, Yang Gao ³^,⁴^,⁵
, Xuedong Sun ⁶^,⁷
, Min Chen ³^,⁴^,⁵^,⁸
, Changhuo Cen ³^,⁴^,⁵
, Mengyue Wang ³^,⁴^,⁵
, Nan Wang ³^,⁴^,⁵
, Bowen Liu ³^,⁴^,⁵
, Jiayi Li ³^,⁴^,⁵
, Xiuhong Cui ³^,⁴^,⁵
, Jian Hou ⁹^,^†
, Yuhua Shi ²^,¹⁰
, Fei Gao ³^,⁴^,⁵^,⁸^,^†

Author information +

¹. Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China

². Department of Reproductive Medicine, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

³. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

⁴. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China

⁵. University of Chinese Academy of Sciences, Beijing, China

⁶. Eastern Department of Neurology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

⁷. Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China

⁸. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China

⁹. State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, China

¹⁰. Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China

houjian@cau.edu.cn

gaof@ioz.ac.cn

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Abstract

As major somatic cells in the testis, Sertoli cell development is precisely regulated by numerous factors, and aberrant development of these cells is associated with male reproductive diseases. JNK signalling is evolutionarily conserved and involved in multiple critical biological processes. Here, we found that the double knockout of Jnk1 and Jnk2 resulted in aberrant localisation of Sertoli cells at early developmental stages, with most Sertoli cells being lost at later stages. Further studies revealed that the inactivation of JNK signalling caused polarity loss in Sertoli cells. In vitro-cultured Jnk1/2-DKO Sertoli cells exhibited a senescence-associated phenotype. Mechanistic studies demonstrate that JNK signalling is likely involved in establishing Sertoli cell polarity by regulating the expression of TGF-β2, mediated by c-Jun. The senescence of Sertoli cells in JNKs-deficient mice is caused by aberrant proteolysis of P27^KIP1, mediated by c-Myc. This study demonstrates the role of JNK signalling in Sertoli cell development and functional maintenance, which may also represent an aetiology of male infertility in humans.

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Zhiming Shen, Yang Gao, Xuedong Sun, Min Chen, Changhuo Cen, Mengyue Wang, Nan Wang, Bowen Liu, Jiayi Li, Xiuhong Cui, Jian Hou, Yuhua Shi, Fei Gao. Inactivation of JNK signalling results in polarity loss and cell senescence of Sertoli cell. Cell Proliferation, 2025, 58(2): e13760 DOI:10.1002/cpr.13760

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