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Inserm U418, UCBL1, UMR INRA 1245, Hôpital Debrousse, 29 rue Soeur Bouvier, 69322 Lyon Cedex 05, France
Correspondence should be addressed to B Le Magueresse-Battistoni; Email: lemagueresse{at}lyon.inserm.fr
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Abstract |
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 Top Abstract IntroductionGeneral aspects of proteases...Serine proteases and serine...Plasminogen activatorsSERPINsAn overview of the...What potential functions in...Conclusions and future...AcknowledgementsReferences |
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Introduction |
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TopAbstractIntroductionGeneral aspects of proteases...Serine proteases and serine...Plasminogen activatorsSERPINsAn overview of the...What potential functions in...Conclusions and future...AcknowledgementsReferences |
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The gonads emerge as an outgrowth and will develop either as a testis or an ovary, depending on the presence of the Sry gene located on the Y chromosome. In response to Sry, Sertoli cells differentiate. They synthesize the Müllerian-inhibiting substance, and they aggregate to form the cords together with peritubular cells originating from the mesonephros. Subsequently, Leydig cells differentiate in the interstitial milieu and start producing testosterone (Wilhelm et al. 2007). At puberty, dynamic changes are associated with the transformation of the cords into tubules and initiation of spermatogenesis. In adult life, germ cells migrate from the base to the apex of the tubule epithelium while differentiating further. Finally, spermatids are released from the apex of the seminiferous epithelium into the tubular lumen, becoming spermatozoa (Russell 1980).
Previous reports suggested that various proteinases and their cognate inhibitors were involved in this spatiotemporal and highly orchestrated process both during testis development and in adult life (Fritz et al. 1993, Charron & Wright 2005). This review describes our current knowledge on the plasminogen activation system in the testis, and its predicted functions in the establishment and maintenance of the testicular architecture and in the process of spermatogenesis.
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General aspects of proteases and protease inhibitors |
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TopAbstractIntroductionGeneral aspects of proteases...Serine proteases and serine...Plasminogen activatorsSERPINsAn overview of the...What potential functions in...Conclusions and future...AcknowledgementsReferences |
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The activity of proteases is regulated at multiple levels including the level of production, the activation of the protease generally synthesized in an inactive pro-form, and the production of specific inhibitors. Proteases catalyze the hydrolysis of peptide bonds in proteins. The exopeptidases attack only peptide bonds localized at/or near the amino- or carboxy-terminal portion of peptide chains. The endopeptidases, also named the proteinases, catalyze the hydrolysis of internal bonds in polypeptides. They are divided into five classes, i.e., aspartic, metzincins, cysteine, serine, and threonine proteases, depending on their catalytic sites. Analysis of the full repertoire of proteases present in the human, mouse, and rat genomes indicates that serine proteases represent one-third of the proteolytic enzymes in rat (221 out of 626), mouse (227 out of 641), and human (178 out of 561; Puente & Lopez-Otin 2004).
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Serine proteases and serine protease inhibitors (SERPINs) |
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TopAbstractIntroductionGeneral aspects of proteases...Serine proteases and serine...Plasminogen activatorsSERPINsAn overview of the...What potential functions in...Conclusions and future...AcknowledgementsReferences |
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Plasminogen activators |
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TopAbstractIntroductionGeneral aspects of proteases...Serine proteases and serine...Plasminogen activatorsSERPINsAn overview of the...What potential functions in...Conclusions and future...AcknowledgementsReferences |
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At least eight distinct plasmin/plasminogen-binding proteins have been proposed, including 
-enolase, amphoterin, and annexin II. Annexin II is a 36 kDa, calcium-dependent, phospholipid-binding protein that exhibits specific saturable binding for both plasminogen and tPA. It independently binds tPA (but not uPA) and plasminogen, anchoring them with high affinity in close proximity to each other on the cell surface, thus providing an environment in which plasmin production is greatly increased (Kim & Hajjar 2002).
The receptor for uPA (uPAR) is a cysteine-rich, highly glycosylated protein, attached to the cell surface by a COOH-terminal glycosylphosphatidylinositol anchor. Both the inactive single chain and the active two-chain uPA can bind to uPAR with high affinity. The receptor uPAR can also bind the serum and extracellular matrix protein vitronectin, an interaction that requires uPA. In contrast, plasminogen does not bind to uPAR. Although lacking a cytosolic domain, uPAR activates multiple intracellular signaling molecules through a connection with integrins (for example, vitronectin is a ligand of vß3 integrin), G-protein-coupled receptors, and caveolin. These include cytosolic kinase pathways with the activation of intracellular tyrosine kinases, the focal adhesion kinase pathway leading to cytoskeletal reorganization, and intracellular calcium mobilization. In addition, both uPA and uPAR exhibit growth activities independent of their proteolytic activities (Blasi & Carmeliet 2002).
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SERPINs |
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TopAbstractIntroductionGeneral aspects of proteases...Serine proteases and serine...Plasminogen activatorsSERPINsAn overview of the...What potential functions in...Conclusions and future...AcknowledgementsReferences |
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SERPINs targeting serine proteinases have a unique suicide-substrate mechanism through an interaction with proteinases to form covalent complexes that are not dissociable when boiling in SDS but are sensitive to nucleophiles. Such a mechanism is based on a dramatic conformational change in the SERPIN. Thus, the trapped complex is irreversible in nature. In addition, several SERPINs including the SERPINs A5, E1, and E2 are activated by binding to negatively charged glycosaminoglycans. The resulting enhancement in the rates of proteinase inhibition can be up to several 1000-fold suggesting that glycosaminoglycans are rate-limiting factors at sites of SERPIN action. In the case of the three aforementioned SERPINs, the mechanism involves bridging in which glycosaminoglycans bind both SERPIN and proteinase to bring them into an appropriate interaction (Pike et al. 2005).
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An overview of the repertoire of the plasminogen/ plasmin system in the testis |
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TopAbstractIntroductionGeneral aspects of proteases...Serine proteases and serine...Plasminogen activatorsSERPINsAn overview of the...What potential functions in...Conclusions and future...AcknowledgementsReferences |
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(IL1), and tumour necrosis factor- (TNF; Fig. 1
). PAs are also positively regulated by germ cells both in coculture or through the addition of germ cell-conditioned media. However, the simultaneous addition of anti-FGF2 or anti-TNF antibodies together with the germ cell-conditioned media does not abolish the effects, indicating that the factors active in stimulating PAs are neither FGF2 nor TNF (Fig. 1 and unpublished data).
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The binding of uPA to its receptor promotes cell adhesion by increasing the affinity of uPAR for vitronectin (Dellas & Loskutoff 2005, Lijnen 2005). It is thus of interest that vitronectin has been identified in early spermatids (Fig. 2) and that PAI-1 is a Sertoli and a peritubular cell product (Fritz et al. 1993, Le Magueresse-Battistoni et al. 1998). Indeed, Sertoli cell PAI-1 might regulate spermatid adhesion through competing with uPAR in binding to vitronectin. As for the PAs, PAI-1 is highly regulated by FSH (negatively) and locally produced cytokines (positively by transforming growth factor-ß1 (TGFß1), FGF2, and TNF; Fritz et al. 1993, Le Magueresse-Battistoni et al. 1997, 1998, Charron & Wright 2005). In contrast, PAI-3 (SERPINA5) is up-regulated by FSH and testosterone (Anway et al. 2005, Meachem et al. 2005, Denolet et al. 2006). It is noteworthy that the serine proteinases eppin and the SERPINs A3n and A12n are also up-regulated by androgens (Denolet et al. 2006).
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Few studies have explored the contribution of Leydig cells to the testicular protease repertoire. It has been reported that Leydig cells express various serine proteases and complementary inhibitors. For some of them, Leydig cells are the unique site of expression in the testis, i.e., the neurotrypsin and kallikreins 21, 24, and 27 (Matsui & Takahashi 2001, Puente & Lopez-Otin 2004). Interestingly, luteinizing hormone (LH)–hCG regulates several serine proteases and inhibitors identified in Leydig cells (including urokinase, matriptase-2, kallikrein-21, HAI-2, and PCI; Odet et al. 2006), indicating that common transcriptional signals may drive the expression of these molecules. Furthermore, kallikreins are regulated by testosterone and estradiol (Matsui & Takahashi 2001, Eacker et al. 2007).
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What potential functions in testicular physiology? |
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TopAbstractIntroductionGeneral aspects of proteases...Serine proteases and serine...Plasminogen activatorsSERPINsAn overview of the...What potential functions in...Conclusions and future...AcknowledgementsReferences |
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Growth factor or receptor activation, receptor shedding, and proteinase activation
Testicular proteases and antiproteases probably display a unique function in delivering growth factors trapped in the ECM, activating growth factors or growth factor receptors, or (and this remains to be demonstrated) in the shedding of transmembrane receptors, generating soluble forms that would act as dominant negatives and impede the normal transducing pathway following ligand binding to its receptor. For example, FGF2, which is deeply involved in testicular physiology (see Ref. in El Ramy et al. 2005), does not contain a sequence signal for secretion, and it has been proposed that following environmental stimuli, FGF2 is released from the ECM through the action of proteases, allowing it to bind to specific transmembrane FGF receptors and transduce a signal (Powers et al. 2000). It is also shown that uPA activates (at least in tubo) pro-TGF-ß and pro-HGF, two decisive growth factors in testicular physiology (Catizone et al. 2001, Itman et al. 2006). Additionally, an extensive network of proteases and inhibitors are influenced by the PA system, the largest group being the matrix metalloproteinases (MMPs) and their respective inhibitors the tissue inhibitors of MMPs (TIMPs; Page-McCaw et al. 2007). Several of them are produced in the testis, including the gelatinases MMP2 and MMP9. Interestingly, MMPs 2 and 9 are regulated strongly by cytokines and weakly (MMP2) or not regulated (MMP9) by hormones (Fritz et al. 1993, Longin et al. 2001, Charron & Wright 2005, Wong & Cheng 2005), indicating that their activity may be secondary to PA activation.
ECM matrix synthesis and remodeling
In the testis, the importance of ECM was evidenced with the finding that male infertility is associated with abnormal thickening of the basement membrane surrounding the seminiferous tubules (also found in aged testes and in Klinefelter patients; de Kretser et al. 1975). Indeed, the basement membrane is the structural basis of testis cord organization in the developing gonad; and in adult life it is essential for the maintenance of the differentiated functions of Sertoli cells (Dym 1994, Griswold 1998). Conversely, much less is known of the ECM matrix surrounding Leydig cells (Kuopio & Pelliniemi 1989).
Testis cord formation
Originally, the genital ridge is composed of primordial germ cells and a thickened layer of coelomic epithelium. When the indifferent gonad has an XY genotype, SRY induces a cascade of gene expression which results initially in the migration of mesenchymal cells as well as endothelial cells from the adjacent mesonephros, and the formation of a basement membrane between the epithelializing Sertoli cells and the mesenchymal peritubular cells. No migration occurs in case of an XX gonad (Brennan & Capel 2004). Such a migration is accompanied by extensive restructuring. Accordingly, major sex-related differences in the distribution of ECM components and the expression of proteases and inhibitors have been reported, including the SERPINs E2 and A5 (Nef et al. 2005, Wilhelm et al. 2007), and TIMP-1 (Guyot et al. 2003).
Testis growth and lumen formation
The prepubertal period is characterized by a rapid growth of the testis, the transformation of the seminiferous cords into tubules, and the initiation of spermatogenesis. Specifically, tight junctions are formed between neighboring Sertoli cells, thus creating the blood–testis barrier, and cords develop a lumen, becoming tubules. Accordingly, Sertoli cells accommodate their cytoskeleton to support additional spermatogenic cell types as spermatogenesis is initiated, and tubules increase in diameter as well as in length. Strong arguments have been given that not only tPA (Fritz et al. 1993) and the growth factors HGF and FGF2, but also basement membrane components (specifically laminin; Skinner 2005), are critically involved in these substantial prepubertal changes. In addition, recent data illustrated that ECM components regulate the expression of tight junction proteins and the formation of a lumen in concert with MMP9 and its inhibitor TIMP-1 (Wong & Cheng 2005). Inasmuch as both HGF and FGF2 must be activated (see above), that PAs activate pro-MMPs including MMPs 2 and 9, and that both MMPs and PAs degrade laminin, fibronectin, and collagen IV – i.e., the major basement membrane components – the plasminogen activation system occupies a central position in assisting remodeling necessary to support the rapid and extensive growth of the prepubertal testis.
Spermatogenesis and the apical migration of germ cells towards the lumen
Different authors have been interested in the understanding of the dynamics of spermatogenesis, which relies on the passage of the blood–testis barrier (translocation) and the release of the elongated spermatids at the apex (spermiation). The description of the testis barrier is beyond the scope of this review and has been treated recently (Wong & Cheng 2005). However, it is noteworthy that the testis barrier is unique when compared with other blood–tissue barriers (e.g., blood–brain and blood–retina barriers), as it is composed of gap junctions, desmosomes, tight junctions, and ectoplasmic specializations, precluding that the passage of germ cells requires a finely tuned process not disturbing the integrity of the testis barrier, which would provoke a pathological arrest of spermatogenesis. Since this situation is reminiscent of cell migration across the ECM, different authors have concentrated their efforts in determining the composition of the junctions, most specifically those that are restricted to testis, i.e., the ectoplasmic specializations, and the way junctional proteins are transcriptionally and post-transcriptionally regulated. It was also reasonable to think that proteases which act like scissors would help germ cells in migrating along Sertoli cell membranes, and that specific inhibitors would restrict the activity of the proteases in a finely tuned regulatory fashion to preserve homeostasis. Therefore, a list of the cytokines, proteases, and inhibitors present at the right time and in the right place has been tentatively established (Charron & Wright 2005, Xia et al. 2005).
First evidence came from the demonstration that the PAs were expressed as a function of the stages of the seminiferous epithelium, and an increased PA activity was found at the time of translocation and spermiation at stages VII and VIII (Fritz et al. 1993). Interestingly, immunostaining of 2-macroglobulin (a protease inhibitor with a large spectrum of inhibitory activities against proteinases) concentrated at stages I–VI, thus prior spermiation indicating that 2-macroglobulin may protect the integrity of the seminiferous epithelium against excessive proteolysis (Wong & Cheng 2005). In addition, the enhancement of Sertoli PA activity (and of the cysteine protease cathepsin L; Charron & Wright 2005) was evidenced in cocultures of Sertoli cells and germ cells (Fig. 1B and C
), and this correlated in time with the dynamics of assembly/disassembly of the de novo adherent junctions forming between the cultured Sertoli cells. Furthermore, the expression of not only 2-macroglobulin but also cystatin (a cathepsin L inhibitor) in the coculture model was consistent with the idea that proteases and their corresponding inhibitors were working synergistically, supporting the evidence that they may be involved in the adherence of germ cells to Sertoli cells and the subsequent formation of intercellular junctions (Charron & Wright 2005, Wong & Cheng 2005). These data are also in line with previous findings reporting that protease-sensitive elements of unknown nature hold spermatids and Sertoli cells together (Russell 1980).
Spermiation, i.e., extrusion of elongated spermatids in the lumen, is the alternate major event that occurs during stages VII and VIII. It is followed by the phagocytosis of the cytoplasts shed from the elongated spermatids, which are called the residual bodies (Russell 1980). An in vitro model has been established in the past where residual bodies (recovered by elutriation of a mixed germ cell preparation) are phagocytosed by Sertoli cells with kinetics comparable to the in vivo situation. Using such an in vitro model, it was demonstrated that phagocytosis of residual bodies resulted in an interleukin 1-dependent enhancement of Sertoli cell PA expression and activity (Sigillo et al. 1998). Interestingly, interleukin 1 production is enhanced upon phagocytosis of residual bodies (Jégou et al. 1995), and interleukin 1 is known to stimulate DNA synthesis in spermatogonia and spermatocytes. Thus, residual bodies upon phagocytosis could trigger the induction of Sertoli interleukin 1, which would lead to the enhancement of the PA activity facilitating germ cell migration in the adluminal compartment and their entry into meiosis, and in the stimulation of germ cell proliferation preceding the initiation of a new wave of spermatogenesis. Therefore, the synchronization process of the spermatogenesis cycle may depend on a proteolytic message (as summarized in Fig. 3), revisiting the pioneering hypothesis of Regaud and Roosen-Runge (referenced in Jégou et al. 1995, Sigillo et al. 1998). Two other cytokines have proven to be essential at least in the passage of the testis barrier by preleptotene spermatocytes. These are TGFß3 and TNF, and TNF enhances uPA dramatically (Fig. 1A). Recent reviews have focused on these cytokines in the testis (Wong & Cheng 2005, Xia et al. 2005).
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). It remains to be determined whether claudins are substrates for either PAs or MMPs, and what is their expression level in the SERPINA5-deficient testes.
Therefore and collectively, it appears that germ cells that do not bear classic characteristics of migrating cells regulate their own progression within the seminiferous epithelium, through a modulation of the expression pattern of the proteases and inhibitors produced by Sertoli cells as exposed in Fig. 3, supporting the hypothesis that Sertoli cells act as facilitators of migration adding a new testosterone-dependent function to these nurse cells.
Proteolysis and steroidogenesis
Different arguments emphasize a role of ECM in the capacity of Leydig cells to respond to LH–hCG in vitro, and thus indirectly of a role of proteases and inhibitors. For instance, it was shown that fibronectin and collagen IV induce down-regulation of the steroidogenic response to gonadotropins (Diaz et al. 2005). Furthermore, TGFß, known to cause augmented fibronectin deposition and to elicit cytoskeletal changes in Leydig cells similar to those evidenced when these cells are cultured on plates pre-coated with fibronectin, antagonizes gonadotropin steroidogenic action in Leydig cells (Dickson et al. 2002). Finally, we recently demonstrated that Leydig cells exhibit two immediate responses upon LH stimulation: an increased expression of StAR and an increased expression of uPA followed by an increased expression of SERPINB2 and tPA (Odet et al. 2006). Thus, two hypotheses (Fig. 3) may be raised. Either the uPA peak signals the immediate matrix environment altering Leydig cell responsiveness to LH or uPA is part of the dialog between the interstitial compartment and the seminiferous epithelium.
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Conclusions and future directions |
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TopAbstractIntroductionGeneral aspects of proteases...Serine proteases and serine...Plasminogen activatorsSERPINsAn overview of the...What potential functions in...Conclusions and future...AcknowledgementsReferences |
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The use of in vitro models coupled with the SiRNA strategy to specifically knock down a protease or its inhibitor should also constitute an elegant means to link morphogen cytokines, ECM components, restructuring events, and proteases. Furthermore, inasmuch as various proteases, inhibitors, and junctional components (e.g., claudins) are under a complex hormonal control via gonadotropins and/or testosterone, and local regulatory control involving cytokines and growth factors, models with reduced testosterone bioavailability or with limited FSH or LH action coupled with microarray studies, such as those recently published (Meachem et al. 2005, Denolet et al. 2006, Tsai et al. 2006, Eacker et al. 2007), should be of tremendous benefit to fully understand the mechanisms that underpin the role of proteases and inhibitors in testis development and function. A challenge for the future will be to identify the full complement of proteases and their regulatory mechanisms. This will enable the design of additional studies to define precisely the role and relative importance of each in the complex steps of testis development and spermatogenesis. Then, the phenotypic effects in gene knockout experiments can be interpreted with the knowledge of their integrated roles and potential for compensatory action.
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Acknowledgements |
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TopAbstractIntroductionGeneral aspects of proteases...Serine proteases and serine...Plasminogen activatorsSERPINsAn overview of the...What potential functions in...Conclusions and future...AcknowledgementsReferences |
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Footnotes |
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TopAbstractIntroductionGeneral aspects of proteases...Serine proteases and serine...Plasminogen activatorsSERPINsAn overview of the...What potential functions in...Conclusions and future...AcknowledgementsReferences |
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  S. Mazaud-Guittot, E. Meugnier, S. Pesenti, X. Wu, H. Vidal, A. Gow, and B. Le Magueresse-Battistoni Claudin 11 Deficiency in Mice Results in Loss of the Sertoli Cell Epithelial Phenotype in the Testis Biol Reprod, January 1, 2010; 82(1): 202 - 213. [Abstract] [Full Text] [PDF]
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 V. Dubois, C. Van Ginneken, H. De Cock, A.-M. Lambeir, P. Van der Veken, K. Augustyns, X. Chen, S. Scharpe, and I. De Meester Enzyme Activity and Immunohistochemical Localization of Dipeptidyl Peptidase 8 and 9 in Male Reproductive Tissues J. Histochem. Cytochem., June 1, 2009; 57(6): 531 - 541. [Abstract] [Full Text] [PDF]
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J. S. Young, J. A. Guttman, K. S. Vaid, and A. W. Vogl Tubulobulbar Complexes Are Intercellular Podosome-Like Structures That Internalize Intact Intercellular Junctions During Epithelial Remodeling Events in the Rat Testis Biol Reprod, January 1, 2009; 80(1): 162 - 174. [Abstract] [Full Text] [PDF]
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 S. Mazaud Guittot, A. Verot, F. Odet, M.-A. Chauvin, and B. le Magueresse-Battistoni A comprehensive survey of the laminins and collagens type IV expressed in mouse Leydig cells and their regulation by LH/hCG Reproduction, April 1, 2008; 135(4): 479 - 488. [Abstract] [Full Text] [PDF]
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