MAP4K4/JNK Signaling Pathway Stimulates Proliferation and Suppresses Apoptosis of Human Spermatogonial Stem Cells and Lower Level of MAP4K4 Is Associated with Male Infertility

Abstract

Spermatogonial stem cells (SSCs) serve as a foundation for spermatogenesis and they are essential for male fertility. The fate of SSC is determined by genetic and epigenetic regulatory networks. Many molecules that regulate SSC fate determinations have been identified in mice. However, the molecules and signaling pathways underlying human SSCs remain largely unclear. In this study, we have demonstrated that MAP4K4 was predominantly expressed in human UCHL1-positive spermatogonia by double immunocytochemical staining. MAP4K4 knockdown inhibited proliferation of human SSCs and induced their apoptosis. Moreover, MAP4K4 silencing led to inhibition of JNK phosphorylation and MAP4K4 phosphorylation at Ser801. RNA sequencing indicated that MAP4K4 affected the transcription of SPARC, ADAM19, GPX7, GNG2, and COLA1. Interestingly, the phenotype of inhibiting JNK phosphorylation by SP600125 was similar to MAP4K4 knockdown. Notably, MAP4K4 protein was lower in the testes of patients with non-obstructive azoospermia than those with normal spermatogenesis as shown by Western blots and immunohistochemistry. Considered together, our data implicate that MAP4K4/JNK signaling pathway mediates proliferation and apoptosis of human SSCs, which provides a novel insight into molecular mechanisms governing human spermatogenesis and might offer new targets for gene therapy of male infertility.

UBR4 deficiency causes male sterility and testis abnormal in Drosophila

“…By linking the results with the GSEA, the results suggest that activation of the MAPK signaling pathway has an important role in key genes such as UBR4, affecting male sterility. According to the current study, the MAPK-JNK signaling pathway regulates a variety of important physiopathological effects such as cell proliferation, differentiation, stress, and inflammatory responses (48,49). Importantly, MAPK signaling regulates male fertility and plays multiple roles in various biological processes in germ cells and is closely linked to processes such as germ cell apoptosis and epididymal maturation (50).…”

“…Importantly, MAPK signaling regulates male fertility and plays multiple roles in various biological processes in germ cells and is closely linked to processes such as germ cell apoptosis and epididymal maturation ( 50 ). More specifically, the MAP4K4-JNK signaling pathway stimulates the proliferation of human spermatogonial stem cells and inhibits apoptosis, which is closely associated with male infertility ( 51 ). Thus, the MAPK pathway consisting of these downstream genes may be a key part of the mechanism linking the action of genes such as UBR4.…”