Mitogen-activated protein kinases in male reproductive function

Abstract

Recent studies have shown that male reproductive function is modulated via the mitogen-activated protein kinase (MAPK) cascade. The MAPK cascade is involved in numerous male reproductive processes, including spermatogenesis, sperm maturation and activation, capacitation and acrosome reaction, before fertilization of the oocyte. In this review, we discuss the latest findings in this rapidly developing field regarding the role of MAPK in male reproduction in animal models and in human spermatozoa in vitro. This research will facilitate the design of future studies in humans, although much work is needed before this information can be used to manage male infertility and environmental toxicant-induced testicular injury in men, such as blood-testis-barrier disruption. Male reproductive health and the involvement of the mitogen-activated protein kinase pathwayMale infertility and subfertility have been attributed to poor semen quality and/or sexual dysfunction. Abnormal semen quality includes reduced sperm counts and defects in the morphology, genetic content or motility of spermatozoa, whereas sexual dysfunction refers to impotence or defects in ejaculation [1,2]. The causative agents for abnormal semen quality are numerous and include heat, physical insults to testicles, radiation, alcohol and/or drug abuse, cigarette smoking and environmental toxicants. Heavy metals (e.g. cadmium and lead) and some drugs, such as chemotherapeutic compounds and antibiotics, are also known to impair fertility [1]. Even though the direct association of the mitogen-activated protein kinase (MAPK) pathway and reproductive dysfunction in men remains to be established, studies in animal models have indicated that the MAPK pathway is often involved in disrupting spermatogenesis and other functions of germ cells or Sertoli cells (see Glossary). This, in turn, leads to a decline in semen quality and fertility.In this article, the participation of the MAPK pathway in various processes leading to abnormal semen quality is explored, as well as its role in normal spermatogenesis and germ cell functions. We also suggest that targeting kinases in the MAPK pathway might have potential for treating or managing male reproductive dysfunction. To assist the conception of couples with fertility problems, in vitro fertilization and intrauterine insemination are commonly used. Members of the MAPK pathway might serve as therapeutic targets to reverse the decline in semen quality and fertility as a result of disruption of sperm function or after testicular injury such as a disruption of the blood-testis barrier (BTB) induced by environment toxicants (e.g. cadmium). Furthermore, the MAPK pathway has been shown to be involved in the differentiation, maturation, and function of male germ cells. Kinases in the MAPK pathway might therefore also have potential for investigation as candidate targets for male contraception. Overview of the MAPK signaling pathwayThe MAPK pathway is known to have an important role in the signal transduction of many cellular ...

Systematic Analysis of the Phosphoproteome and Kinase-substrate Networks in the Mouse Testis

“…Previously, it was reported that the MPAKs play an important role in spermatogenesis (6), with MAPK1 predicted to phosphorylate 47 (ϳ44%) proteins in the sub-KSPN (supplemental Fig. S4).…”

“…Because phosphorylation, an important and ubiquitous post-translational modification (PTM) 1 , is one of the most critical regulatory mechanisms of the cell cycle (5), which is particularly active during spermatogenesis, a number of pioneering studies have contributed to our understanding of phosphoregulation in spermatogenesis. For example, mitogen-activated protein kinases (MAPKs) such as ERK1/2, were found to play an important role in ectoplasmic specialization dynamics during spermatogenesis (6). As important regulators of the cell cycle (7,8), the POLOlike kinases (PLKs) especially PLK1, were found to be required at multiple stages of spermatogenesis (9 -12).…”

The Blood-Testis Barrier and Its Implications for Male Contraception

“…Introduction. Studies in multiple epithelia and/or blood-tissue barriers in various organs (e.g., kidney, small intestine, brain, eyes), including the BTB in adult mammalian testes, have demonstrated the role of cytokines, such as TNF␣, interferon-␥, TGF-␤2/-␤3, IL-1␣, and IL-12, in regulating TJ permeability barrier function under normal and pathological conditions (e.g., inflammation, tumorigenesis) (Walsh et al, 2000;Xia et al, 2005a;Lui and Cheng, 2007;Li et al, 2008Li et al, , 2009aCapaldo and Nusrat, 2009;Turner, 2009;Marchiando et al, 2010a;Roberson and Bowcock, 2010;John et al, 2011). It is noted that endocytic vesicle-mediated protein trafficking events (e.g., endocytosis, transcytosis, recycling, or intracellular protein degradation mediated by endosome-and/or ubiquitin-dependent pathways) that determine the levels of integral membrane proteins at the TJ barrier play a critical role in modulating the adhesive status of cell adhesion protein complexes (e.g., cadherins, occludins, JAMs, claudins) at the barrier, and protein endocytosis can be mediated by either clathrinor caveolae-dependent pathways or macropinocytosis (Tuma and Hubbard, 2003;Maxfield and McGraw, 2004;Mehta and Malik, 2006;Clague and Urbé, 2010;Golachowska et al, 2010;Hsu and Prekeris, 2010).…”

Transcriptome profiling of the developing postnatal mouse testis using next-generation sequencing

“…The MAPK (Mitogen-activated protein kinase) pathway is involved in many male reproductive processes, including spermatogenesis, sperm maturation and activation, adhesion of Sertoli cells and spermatogenic cells, and dynamics of the blood-testis barrier [71]. Transcripts of rat Pdgfrb are detected at embryonic day 18 (E18), reach high levels on 5 dpn, and then decline to lower levels [72].…”