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Review
. 2009 Apr;15(4):159-68.
doi: 10.1016/j.molmed.200902002. Epub 2009 Mar 18.

Mitogen-activated protein kinases in male reproductive function

Affiliations
Review

Mitogen-activated protein kinases in male reproductive function

Michelle W M Li et al. Trends Mol Med. 2009 Apr.

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.

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Conflict of interest statement

Disclosure statement

The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
The core components of the MAPK signaling pathway. The MAPK pathway transduces signals from external stimuli (e.g. when testicular cells are exposed to environmental toxicants, such as cadmium, or cytokines, such as TGF-β3) to cells (e.g. Sertoli and/or germ cells) so that appropriate physiological responses can occur. When induced by external stimuli, as shown in the left-hand box, there is a sequential activation of MAP4Ks and MAP3Ks (e.g. MEKK, TAO, Mos, Raf); see the right-hand box, which shows examples of members of the MAPK cascade and some commonly used inhibitors. Phosphorylated MAP3Ks will activate MAP2Ks (e.g. MEK4/7, MEK3/6, MEK1/2, MEK5). Upon activation by MAP3Ks, dual-specificity MAP2Ks (e.g. MEK4/7, MEK3/6, MEK1/2, MEK5) will in turn activate MAPKs (e.g. JNK1–3, p38 MAPKα–δ, ERK1/2, ERK5) directly through phosphorylation of both a Tyr and a Ser or Thr residue. Different stimuli affect different components of the MAPK pathway, and different effectors of MAPK will be activated for different physiological responses. Some of the commonly used inhibitors that block specific MAPKs are shown. Inhibitors that are shown in red are used mostly for basic research because their therapeutic developments were not continued due to undesirable side effects. The chemical names of the inhibitors listed are as follows: SP600125, anthra[1–9-cd]pyrazol-6(2H)-one; SB202190, 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]phenol; SB203580, 4-[5-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl]pyridine; SB242235, 5-[5-(4-fluorophenyl)-3-piperidin-4-yl-3H-imidazol-4-yl]-2-methoxy-pyrimidine; SCIO-469, 2-[6-chloro-5-[[(2R,5S)-4-(4-fluorobenzyl)-2,5-dimethylpiperazin-1-yl]carbonyl]-1-methyl-1H-indol-3-yl]-N,N-dimethyl-2-oxoacetamide; Sorafenib, 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)-butadiene; PD98059, 2′-amino-3′-methoxyflavone. Abbreviations: Mos, oocyte maturation factor; Raf, proto-oncogene serine/threonine protein kinase; MEKK, MAPK/ERK kinase kinase, also known as MAP3K, mitogen-activated protein kinase kinase kinase 1, a serine/threonine kinase; TAO, thousand and one amino acid protein.
Figure 2
Figure 2
The role of MAPK in regulating cell adhesion function and BTB dynamics in the testis. (a) A schematic drawing of the cross-section of a seminiferous tubule showing the seminiferous epithelium. The seminiferous epithelium is composed of only Sertoli cells and germ cells (e.g. spermatogonia, spermatocytes, round spermatids, elongating spermatids, and elongated spermatids) at different stages of their development during spermatogensis. The endothelium is encircled by the basement membrane, which is a modified form of the extracellular matrix. The BTB (blue-boxed area) divides the epithelium into the basal and adluminal compartments. Primary preleptotene spermatocytes (diploid, 2n) traverse the BTB at stages VIII and IX of the epithelial cycle (see Glossary) while differentiating into leptotene and zygotene spermatocytes. Once behind the BTB, meiosis occurs at stage XIV of the epithelial cycle in rat testes, wherein diplotene spermatocytes (tetraploid, 4n) undergo two cycles of reduction divisions (meiosis I and meiosis II) to form round spermatids (haploid, 1n). All the postmeiotic germ cell development, namely spermatids that undergo spermiogenesis via steps 1 through 19, is segregated from the systemic circulation by the immunological barrier conferred by the BTB. As such, the BTB is a unique and physiologically significant ultrastructure for the maintainence of spermatogenesis. (b) Testicular insults, including exposure to environmental toxicants (e.g. cadmium) or drugs, might induce a perturbation of germ cell adhesion via the p38 and ERK MAPK pathways. (Note, the anchoring junction between the Sertoli cell and germ cell is crucial to maintain: (i) proper communication between these cells for germ cell development, because germ cells must rely on Sertoli cells for both structural and nourishment support; and (ii) proper orientation, because without the intact anchoring junction, germ cells either undergo apoptosis or detach from the epithelium prematurely.) (c) Testicular insults might also cause a disruption of the BTB via the p38 and ERK MAPK pathways. (Note, the BTB, unlike other blood–tissue barriers such as the blood–brain barrier, is composed of co-existing tight and anchoring junctions instead of only tight junctions, which is crucial to maintain the immunological barrier function at the BTB during anchoring junction restructuring through a yet-to-be defined mechanism.) The disruption of germ cell adhesion and BTB function might potentially be blocked or modulated with the use of small molecule inhibitors against kinases of the MAPK cascade (indicated with dashed arrows).

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