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Review |
School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, People's Republic of China
(Correspondence should be addressed to W M Lee; Email: hrszlwm{at}hku.hk)
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Abstract |
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) on cell junction restructuring in the testis and the molecular mechanisms.
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Introduction |
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Hormones and cytokines are known biomolecules that regulate a wide spectrum of cellular functions in different tissues such as testes. In this review, we shall highlight the molecular mechanisms by which testosterone, FSH, transforming growth factor-βs (TGF-βs), and tumor necrosis factor- (TNF-) exert their effects in regulating cell junction restructuring pertinent to spermatogenesis. The architecture of cell junctions in the testis has been extensively reviewed elsewhere (Lui & Lee 2006, Sofikitis et al. 2008, Wong et al. 2008). Readers are strongly encouraged to read those reviews for a more comprehensive view of the topic.
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Testosterone |
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Several in vivo models including hormone-suppression, hormone-restoration and hypophysectomy are available for the study of the hormonal regulation of spermatogenesis by testosterone (Huang et al. 1987, Sun et al. 1989, O'Donnell et al. 1994). Extensive studies have been performed in the past two decades using the suppression and restoration models to understand how testosterone affects spermatogenesis. Testosterone has been shown to exert its effect to control the fate of developing germ cells, in particular the round spermatids (Sun et al. 1990, McLachlan et al. 1994). For instance, the suppression of intratesticular testosterone by testosterone and estradiol implant could interrupt the conversion of round spermatids to elongated spermatids between stages VII and VIII, but could be restored to normal upon high-dose testosterone treatment (O'Donnell et al. 1994). Subsequent studies confirmed that the absence of the elongated spermatids in testosterone-suppressed rats was due to the fact that round spermatids were prematurely detached from the epithelium (O'Donnell et al. 1996). These studies suggest that testosterone affects the adhesive function between round spermatids and Sertoli cells, leading to the sloughing of round spermatids from the epithelium.
The detailed mechanism of how testosterone alters the adhesive function has been recently unraveled. Two protein complexes linking between round spermatids and Sertoli cells at the apical ES, the cadherin/cadherin and 6β1-integrin/laminin
3 interlocks, are the affected targets in the testosterone-suppression model (Wong et al. 2005, Zhang et al. 2005b). In normal rat testis, actin-linked N-cadherin/β-catenin complexes in both Sertoli cell and round spermatid join together to form intact actin-based cadherin/cadherin AJ interlocks at the cell–cell surface, and such interaction is tightly controlled by kinases and phosphatases such as c-src and myotubularin-related protein 2 (Zhang et al. 2005a; Fig. 1). For the 6β1-integrin/laminin3 interlock, the interaction of peripheral proteins, focal adhesion kinase (FAK) and c-src, with β1-integrin on the Sertoli cell side is important to maintain the integrity of the 6β1-integrin/laminin3 interlock (Yan & Cheng 2006).
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6β1-integrin/laminin3 interlock at the Sertoli cell/spermatid interface (Wong et al. 2005). Taken collectively, the two major junction interlocks at the apical ES are seriously disrupted in testosterone-suppressed testis and testosterone thus plays a major role to regulate the adhesive function between Sertoli cells and round spermatids via its action on the protein complexes at the apical ES. Apart from its role to regulate the dynamics of the apical ES and spermiation in the testis, recent studies have demonstrated that testosterone (2x10–7 M) also controls the bioavailability of several junction proteins at the BTB by accelerated endocytosis (Yan et al. 2008a). Although the concentration of testosterone used in this study was greater than the Kd of AR (2–5x10–10 M), the results obtained in the study are of physiological significance (Wilson & French 1976) since this is the testosterone concentration in the testis which is 100-fold that of the serum. The reason for the presence of a supraphysiological testosterone level (greater than Kd of the AR) in the testis is unknown; perhaps this is reflected by a different regulation of testosterone entry to the cell. In the rat testis, the androgen-binding protein that regulates the bioavailability of testosterone in extracellular fluid is produced by the Sertoli cells and found within the seminiferous tubular compartment. However, Yan et al. have found that the addition of testosterone into the Sertoli cell culture having well-established TJ and AJ can accelerate the internalization of junction proteins from the cell surface. Junction proteins including occludin, junctional adhesion molecule-A (JAM-A) and N-cadherin were the target proteins being internalized into the clathrin vesicles and subsequently targeted to early endosomes for transcytosis. It was found that testosterone could enhance the recycling of the internalized junction proteins back to the cell surface (Yan et al. 2008a) and such cycling of junction proteins back and forth between cell surfaces is important in controlling the transient opening of the BTB to allow the migration of spermatocytes. It is postulated that the internalization of BTB junction proteins at the apical end of the migrating spermatocytes facilitates cell movement. Once the spermatocytes move along, testosterone enhances recycling of the internalized junction proteins back to the Sertoli cell surface at the basal region of the spermatocytes to reseal the BTB (Yan et al. 2008a).
Earlier studies by Chung & Cheng (2001) have revealed that testosterone can up-regulate other tight junction components including claudin-11, claudin-1, E-cadherin and β-catenin at the mRNA levels in the rat testis. Until recently, Kaitu'u-Lino et al. (2007) have demonstrated that testosterone regulates claudin-11 expression and promotes the localization of claudin-11 and occludin at Sertoli–Sertoli cell interfaces. Along this line, studies by Meng et al. (2005) have shown that testosterone positively regulates the expression of claudin-3 in mice, which is believed to be a transient component of newly-formed tight junctions at the BTB. Although knockout of claudin-11 causes male infertility in mice (Gow et al. 1999), there is still little definitive data available on the detailed regulatory mechanism of claudin members in the testis by testosterone. Taken collectively, testosterone is a master regulator in controlling the bio-availability of the tight junction proteins at the BTB via post-translational and transcriptional pathways.
Generation of the AR knockout (ARKO) and Sertoli cell-selective (SC) ARKO mice in fact has provided significant insights towards understanding the role of androgen in spermatogenesis (Yeh et al. 2002, Chang et al. 2004, De Gendt et al. 2004, Holdcraft & Braun 2004, Denolet et al. 2006). Mice from these knockout models are all infertile. In particular, it was found that spermatogenic arrest occurred at the pachytene stage in ARKO mice and resulted in severe testis atrophy (80% smaller than wild-type; Yeh et al. 2002); whereas SC ARKO testes (28% smaller than wild-type) displayed spermatogenic arrest at the late spermatocytes/spermatid stages (De Gendt et al. 2004, Holdcraft & Braun 2004). The numbers of round spermatids and elongated spermatids in SC ARKO mice were reduced to 0–3% respective to the wild-type (De Gendt et al. 2004). The fact that SC ARKO mice present a testicular phenotype similar to that of the testosterone-suppressed rodent model further strengthens the idea that testosterone and its receptor play specific roles in Sertoli–germ cell adhesion in the seminiferous epithelium. With the advance of microarray technique, Denolet et al. have analyzed and compared the gene profiles of wild-type and SC ARKO mice. A spectrum of genes related to junction restructuring, including structural components (claudin and nectin-like molecule-1) and regulatory components (serine-type protease inhibitors), has been found to be differentially expressed in the SC ARKO mice respective to the wild-type (Denolet et al. 2006), which further suggests that testosterone is indeed a key player in modulating junction dynamics in the testis. It is apparent that testosterone is not only involved in round spermatid-Sertoli cell adhesion at the apical ES, but also functions as a positive regulator to maintain the integrity of the BTB.
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FSH and estrogen |
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Rat models having both intratesticular testosterone and FSH suppression have been used to study the effect of hormonal suppression on spermiation. Mature spermatids are attached to Sertoli cells via the apical ES. During spermiation, the apical ES are likely to be removed, which is subsequently followed by the formation of tubulobulbar complex (TBC) and the detachment of spermatids from the Sertoli cells. It was found that T+FSH-suppression severely interrupted spermiation in the rats, more significantly than T- or FSH-suppression alone (Saito et al. 2000, Beardsley & O'Donnell 2003). Immunohistochemistry analyses have shown that the β1-integrin remained associated with the elongated spermatids in the T+FSH-suppressed testis after the removal of the apical ES. The association of the β1-integrin in mature spermatids was the likely cause of spermiation failure (Beardsley & O'Donnell 2003, Beardsley et al. 2006). These data suggest that testosterone and FSH act synergistically to support spermiation possibly by mediating the dissociation of the β1-integrin in mature spermatids at spermiation. Another in vivo study in hypophysectomized rats has shown that concurrent testosterone plus FSH treatment, but not testosterone alone, is able to restore normal spermiogenesis and that this restoration is associated with the reorganization of F-actin and vinculin at the ES (Muffly et al. 1994). Other than rat models, studies on Djungarian hamsters have also demonstrated that exogenous supply of FSH to short-day photoperiod (8 h light:16 h darkness) hamsters whose gonadotropins are suppressed could restore the localization of junction proteins such as actin and espin at the apical ES, and claudin-11 and zonula occludens-1 (ZO-1) at the basal region of the seminiferous epithelium (Tarulli et al. 2006). Using the same animal model, Tarulli et al. (2008) have recently found that similar to claudin-11, claudin-3, occludin and JAM-A can rapidly be reorganized at the BTB upon FSH replacement. These results strongly suggest that in addition to spermiation, FSH regulates the integrity and functionality of the BTB via reorganization and relocalization of junction proteins.
An in vitro study has confirmed that FSH is important to stimulate the relocation of ES proteins such as epsin and in the presence of FSH, cultured Sertoli cells are capable of forming not only the classical AJs, but also the AJ belts and the testis-specific ES which contains actin and epsin (Sluka et al. 2006). Other than ES proteins, FSH also regulates the tight junction proteins such as coxsackievirus and adenovirus receptor (CAR) and claudin-11 in the testis (Mirza et al. 2007). It has been reported that FSH up-regulates the CAR mRNA in cultured immature rat Sertoli cells. However, in claudin-11 expression, rat and mouse Sertoli cells responded to FSH treatment oppositely. It was found that FSH could partially stimulate claudin-11 mRNA in cultured rat Sertoli cells, and it inhibited the expression of claudin-11 mRNA in mouse Sertoli cells (Hellani et al. 2000, Kaitu'u-Lino et al. 2007). Despite the fact that the importance of FSH in regulating junction restructuring has been known for a long time, the molecular mechanism explaining how FSH exerts its effect remains enigmatic. Further studies in this area are highly warranted.
Apart from FSH, the effects of estrogen on spermiation have been recently examined (D'Souza et al. 2008). Confocal microscopic studies have confirmed that administration of 17β-estradiol to rats, which causes a rise in intratesticular 17β-estradiol and suppression of circulating FSH and intratesticular testosterone could result in the disruption of the TBC in elongated spermatids and spermiation failure. It is believed that 17β-estradiol affects the Sertoli cell cytoskeleton and Arp2/3 complex which are critical for de novo polymerization of actin during TBC formation (D'Souza et al. 2008).
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Molecular mechanism of cytokines on regulating junction restructuring in the testis |
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are known to regulate multiple physiological functions including germ cell development, Leydig cell steroidogenesis and extracellular matrix (ECM) biosynthesis in the testis (for reviews, see Lui et al. 2003a, Siu & Cheng 2004). In addition, there is accumulating evidence showing that TGF-βs (TGF-β2 and TGF-β3) and TNF- are actively involved in junction restructuring in the seminiferous epithelium, thus facilitating the movement of developing germ cells. These cytokines are secreted by Sertoli and germ cells in a stage-specific manner. For instance, TGF-β3 and TNF- are expressed at their highest in stages VII–VIII tubules (Lui et al. 2003b, Siu et al. 2003), similar to the expression of the AR. Recent studies have unraveled the molecular mechanism by which these cytokines exert their effects to modulate junction dynamics. In fact, TGF-βs and TNF- regulate the junction restructuring via various control mechanisms at the transcriptional, post-transcriptional and post-translational levels. |
Transforming growth factor-βs |
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While TGF-β3 was found to differentially regulate apical ES and/or BTB junctions, TGF-β2 was shown to reduce the junctional adhesion molecule-B (JAM-B) protein level via transcriptional repression in cultured Sertoli cells (Wang & Lui 2009). In the testis, JAM-B is expressed by Sertoli cells and localized at the apical ES to form interlocks with (JAM-C) for spermatid attachment (Gliki et al. 2004). It was found that TGF-β2 exerted its negative regulatory effects on the JAM-B transcription via activation of Smad proteins. Activated Smad proteins effectively displaced Sp1 proteins from the TGIF motif of JAM-B promoter, resulting in JAM-B repression (Wang & Lui 2009).
It is apparent that the reduction of the junction protein level within cells, either by suppressing de novo protein synthesis or promoting its protein degradation, is an effective approach to modulating junction restructuring. A recent study has shown that TGF-β2 can alter the bioavailability of junction proteins at the cell–cell interface by accelerating protein degradation (Yan et al. 2008a). It has been found that both TGF-β2 and testosterone can accelerate the kinetics of internalization of the BTB proteins from the cell surface. However, the fates of internalized proteins triggered by TGF-β2 and testosterone are entirely different. TGF-β2 accelerates the internalization of integral membrane proteins (such as JAM-A and occludin) via a clathrin-coated pit and targets the internalized proteins into late endosomes for degradation, leading to the disassembly of the BTB; whereas testosterone accelerates the internalization of integral membrane proteins and their transcytosis to form new junction fibrils beneath the migrating spermatocyte (Yan et al. 2008a).
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Tumor necrosis factor-
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is produced by Sertoli and germ cells in the testis and is a crucial cytokine that regulates a wide range of cellular processes in the testis (Mruk & Cheng 2004). It controls steroidogenesis in Leydig cells and survival of germ cells by interfering signaling transduction of the Fas-ligand system (Pentikainen et al. 2001, Hong et al. 2004). Analysis of adult rats having chronically systemic administration of TNF- has uncovered the possible role of TNF- on junction restructuring in the testis (Mealy et al. 1990). It was found that the loss of germ cells from the seminiferous epithelium in this animal model was not due to inflammatory responses. In fact, TNF- exerted its effect on Sertoli–germ cell interface, resulting in premature germ cell loss from the epithelium (Mealy et al. 1990). To elucidate the mechanism on how TNF- perturbs cell junctions between Sertoli and germ cells, Li et al. (2006) have established another in vivo model by local administration of recombinant TNF- into rat testes. It was found that there was a significant increase in FITC diffusion across the BTB in the seminiferous tubules along with the reduction of occludin and ZO-1 protein levels in the testis lysate, which clearly illustrates the disruption of the BTB upon TNF- treatment (Li et al. 2006). Apart from the BTB impairment, TNF- is capable of causing disorganization of the actin bundles and cisternae of endoplasmic reticulum at the apical ES, leading to the release of premature spermatids (Li et al. 2006; Fig. 2).
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. In a recent study, it has been demonstrated that TNF- can act on the CLMP mRNA transcript and destabilize the transcript by promoting the binding of an RNA-binding protein, tristetraprolin, at the 3'UTR region under the activation of the c-Jun N-terminal kinase (JNK) pathway (Sze et al. 2008). This study illustrates that TNF- disassembles TJ proteins at the BTB, possibly including regulation at post-transcriptional level by affecting the mRNA stability (Fig. 2). |
Bioactive peptides released from proteolysis |
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and other cytokines is also proposed to be mediated by collagen fragments resulting from proteolytic cleavages of the ECM proteins (Siu et al. 2003, Yan et al. 2008a). These laminin and collagen fragments that coordinate events within the testis are in fact functioning as paracrine factors. Sertoli cells produce a variety of matrix metalloproteases and tissue inhibitors of metalloproteases (Siu et al. 2003, Siu & Cheng 2004). Studies of the proteolysis and proteolytic fragments in the testis deserve greater attention, as the identification of unique coordination pathways in regulating junction restructuring has the potential for the development of a non-hormonal male contraceptive. |
Concluding remarks |
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Declaration of interest |
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Funding |
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References |
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Received in final form 14 January 2009
Accepted 9 March 2009
Made available online as an Accepted Preprint 9 March 2009
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Abstract
Introduction
