The Emerging Role of Matrix Metalloproteases of the ADAM Family in Male Germ Cell Apoptosis

Ricardo D. Moreno,* Paulina Urriola-Muñoz and Raúl Lagos-Cabré

Departamento de Fisiología; Pontificia Universidad Católica de Chile; Santiago, Chile

Key words: spermatogenesis, apoptosis, metalloprotease, infertility

Constitutive germ cell apoptosis during mammalian sperm- Despite that some data suggest that germ cell apoptosis is autono- atogenesis is a key process for controlling sperm output and to mous (independent of the environment), the role of the Sertoli eliminate damaged or unwanted cells. An increase or decrease cell should not be disregarded, because it may provide important in the apoptosis rate has deleterious consequences and leads survival and/or dead clues to germ cells (see below). Germ cell to low sperm production. Apoptosis in spermatogenesis has been widely studied, but the mechanism by which it is induced apoptosis has been shown to play an important role in control- under physiological or pathological conditions has not been ling sperm output in many species, and in humans it has been 5-10 clarified. We have recently identified the metalloprotease related to infertility. Additionally, it has been proposed that ADAM17 (TACE) as a putative physiological inducer of germ the purported decline in global sperm production is caused by cell apoptosis. The mechanisms involved in regulating the environmental xenoestrogens that induce germ cell apoptosis.11 shedding of the ADAM17 extracellular domain are still far In the same way, a modern lifestyle and the use of underwear has from being understood, although they are important in order been proposed to induce elevated scrotal temperature that may to understand cell-cell communications. Here, we review cause germ cell apoptosis, akin to transient heat stress (43°C for the available data regarding apoptosis during mammalian 15 min) in the testis.12,13 Germ cells undergoing meiosis (sper- spermatogenesis and the localization of ADAM proteins in the matocytes) and diploid spermatogonia are sensitive to heat shock, male reproductive tract. We propose an integrative working ionising radiation, growth factor deprivation and chemotherapeu- model where ADAM17, p38 MAPK, protein kinase C (PKC) 14-18 and the tyrosine kinase c-Abl participate in the physiological tic agents. Many studies have shown the relevance of apopto- signalling cascade inducing apoptosis in germ cells. In our sis in regulating spermatozoa output and in eliminating damaged 5,19-24 model, we also propose a role for the Sertoli cell in regulating germ cells, particularly spermatocytes. Moreover, in seasonal the Fas/FasL system in order to induce the extrinsic pathway of breeding mammals, apoptosis plays an important role in the mas- apoptosis in germ cells. This working model could be applied to sive germ cell depletion observed during the non-breeding sea- further understand constitutive apoptosis in spermatogenesis son.25-27 Therefore, apoptosis is important in physiological and and in pathological conditions (e.g., varicocele) or following pathological conditions, and knowledge of the molecular mecha- environmental toxicants exposure (e.g., genotoxicity or nisms underlying this process may help in developing new phar- xenoestrogens). macological tools in order to modulate fertility (Fig. 1). In this review, we will analyze the available evidence regarding the role of different apoptotic pathways in germ cell apoptosis. In addition, we will review the distribution and localization of matrix Introduction metalloproteases of the ADAM family in the male reproductive tract and discuss the recently discovered role of ADAM17 in the In order to ensure fertility, an important step is the proper differ- initiation of the apoptotic programme in germ cells. entiation and function of spermatozoa. Sperm production relies on physiological and environmental factors, which may attenu- Molecular Mechanisms ate or even totally suppress testicular function (Fig. 1). Massive of Germ Apoptosis Execution germ cell death occurs under physiological conditions (constitutive apoptosis) during the first round of spermatogenesis, which From primitive multicellular organisms to higher vertebrates, seems to be vital in order to establish a proper interaction between well-orchestrated cell death events are critical for the removal of germ and Sertoli cells and to eliminate unwanted germ cells.1-3 superfluous cells as a vital part of tissue sculpting during devel- Different experimental approaches have pointed out that germ opment. Physiological cell death enables the elimination of cells undergoing meiosis (spermatocytes) are the main target for unwanted extra cells to maintain cellular homeostasis in devel- apoptosis, in addition to a smaller fraction of spermatogonia.1,4 oped adults, as well as the elimination of harmful cells, or cells with serious cellular or genomic damage.28 Apoptosis is pro- *Correspondence to: Ricardo D. Moreno; Email: [email protected] grammed cell death characterized by several hallmarks such as Submitted: 07/29/11; Revised: 08/27/11; Accepted: 08/29/11 internucleosomal DNA fragmentation, caspase activation and http://dx.doi.org /10.4161/spmg.1.3.17894 externalization of phosphatidyl serine.29,30 In this context, it is

www.landesbioscience.com Spermatogenesis 195 elongating spermatids and Leydig cells.37 In the human, the DR4 receptor is faintly detected in some myoid cells and intense immunoexpression has been detected in Sertoli cells, whereas strong expression is detected in spermatocytes, round and elongated spermatids. The DR5 receptor is highly expressed by spermatocytes, round and elongated spermatids, but not detected in Leydig or Sertoli cells. In the mammalian testis, death receptor ligands such as Trail (DR4 and DR5 ligand) have been shown to be expressed by all germ cells, as well as Sertoli and Leydig cells. On the other hand, Fas ligand (FasL) is expressed by Sertoli cells,38 although other reports have detected it in germ cells.39 Thus, ligand-induced germ cell apoptosis could be triggered in a juxta/paracrine or autocrine fashion upon ligand binding to its cognate receptor. Activation (trimerization) of death receptors in response to ligand binding induces the formation of a multimeric complex Figure 1. Factors affecting germ cell apoptosis in spermatogenesis. named the death-induced complex (DISC), which allows for the activation of procaspase-8 in mice along with caspase-10 in humans.35,40,41 Caspase-8 and/or 10 initiate apoptosis by induc- important to differentiate between apoptosis induction and apop- ing proteolytic processing of caspases-3, -6 and -7.42,43 Among tosis execution. Apoptosis initiation or induction can be defined these, caspase-3 is the main executioner caspase involved in frag- as the molecular signaling events which trigger the extrinsic or mentation of the Golgi apparatus, nuclear lamina and DNA (due intrinsic apoptotic pathways. In this way, events such as protein in part to proteolysis of a DNAse inhibitor) and the decrease in kinase activation, calcium signaling or oxidative stress could be mitochondrial membrane potential.41,44,45 regard at the initiation step of apoptosis. In this way, the activa- Evidence supporting the extrinsic pathway in physiological tion of signaling cascades and their cross-talk produce activation germ cell apoptosis during the first round of spermatogenesis of apoptotic and anti-apoptotic genes (as a defence mechanism). comes from studies showing an increase in levels of the Fas recep- However, a cell with competence to undergo apoptosis is able tor and activation of caspases -8, -3, -2 and -6 in apoptotic germ to reverse this process thanks to the induction of anti-apoptotic cells.46,47 In addition, pharmacological inhibition of caspase-8 genes until the cell passes the “point of no return” and the exe- reduces by more than 50% the number of apoptotic germ cells, cution program is activated.31 Apoptosis execution involves the suggesting an important role of the extrinsic pathway in this pro- activation of caspases, a family of serine proteases with around cess. Nevertheless, these data do not rule out the involvement 14 members, which are synthesized as inactive zymogens and of other death receptors which are found in testes.36,37 However, become active upon specific death stimuli.32 The common strat- male mice harbouring a spontaneous loss of function mutation egy adopted to achieve apical caspase activation is the formation in the Fas gene (lpr mice) or FasL (gld mice) are fertile with of complexes containing several caspase zymogens.33,34 In this normal spermatogenesis, suggesting that the Fas/FasL pathway, apical caspase activation can be induced by the intrinsic way may be dispensable in germ cell apoptosis.48 Despite this, (mitochondrial) pathway or by the extrinsic (cell death receptor) FasL mutant gld (generalized lymphoproliferative disease) mice pathway. Several cellular mechanisms can be recognized in order that lack a functional Fas signaling pathway have a small but to prevent and/or regulate caspase activation. Among these, we significant increase in testis weight and numbers of spermatid could mention: (1) cellular caspase inhibitor expression; (2) cell heads per testis, as compared with wild type mice. In addition, death receptor activation; (3) mitochondrial membrane perme- gld mice show a slightly higher spontaneous incidence of germ ability regulation by Bcl-2 proteins and (4) regulation of mul- cell apoptosis than wild type mice, suggesting that under normal tiprotein caspase-containing protein complexes.29 Therefore, the conditions, the Fas/FasL system could have a role in physiological final balance between pro-apoptotic and anti-apoptotic signals (constitutive) germ cell apoptosis.49 In humans, altered meiotic will define whether or not the cell will activate the executioner and post-meiotic germ cell maturation might be associated with program of apoptosis. an upregulation of Fas gene expression and apoptosis.50,51 Evidence supporting the extrinsic pathway in germ apop- Besides physiological apoptosis, evidence suggests the involve- tosis. The extrinsic pathway is characterized by the activation of ment of the extrinsic apoptosis pathway after exposure to etopo- death receptors such as Fas (CD95/Apo-1) or the tumor necrosis side, ethanol,52 methoxychlor,53 GNRH antagonists,54 maternal factor receptor 1 (TNFR1, also called p55 or CD120a), which and dietary selenium,55 ionising radiation,56,57 zearalenone,58 and have been shown to be expressed by germ cells in the mouse, rat testicular pathologies such as autoimmune orchitis,59 matura- and human testis.35,36 In mouse testes, additional death recep- tion arrest, Sertoli cell-only syndrome60 and cryptorchidism.61 tors such as TRAIL-R1 (DR4) are present in elongating sperma- However, contradictory evidence has been found with the envi- tids and in Leydig cells, while TRAIL-R2 (also known as DR5, ronmental xenoestrogen mono-(2-ethylhexyl)phthalate (MEHP) APO-2 and KILLER) is expressed predominantly by round and

196 Spermatogenesis Volume 1 Issue 3 regarding the role of Fas/FasL.62,63 Therefore, the extrinsic apop- a functional catalytic domain (HExGHxxGXXHD).82-84 So far, totic pathway is activated during germ cell apoptosis. about 20 ADAM genes have been discovered in the human and Evidence supporting the intrinsic pathway in germ cell 37 in the mouse; to date, eight of the latter have been found apoptosis. The intrinsic pathway is characterized by a decrease only as predictions from the genomic sequence.84 ADAM metal- in mitochondrial membrane potential and the release of cyto- loproteases are widely distributed throughout different tissues chrome c, which along with dATP, the cytosolic protein Apaf-1 and at different stages of development. However, the expression and procaspase-9, assembles into a complex called the apopto- pattern and function of specific isoforms are tightly regulated some. Within this complex, procaspase-9 becomes active and during development, cell differentiation, insults and pathological then cleaves caspase-3, connecting the intrinsic and the extrin- conditions. sic pathways.33,34 Mitochondrial membrane permeabilization Proteolytically active ADAMs can shed or cleave a large array is carried out by proapoptotic proteins belonging to the B-cell of substrates.85 The ADAM metalloprotease domain is preceded lymphoma-2 (Bcl-2) family, which encompasses proteins that by a prodomain which is thought to work as an intramolecular promote apoptosis, whereas other members prevent apoptosis.64 chaperone controlling the folding of the catalytic domain. The BCL-2, BCL-x and BCL-w are three anti-apoptotic proteins prodomain (usually around 20 kDa) maintains the protease that interact with and repress the activity of pro-apoptotic prodomain in an inactive state, and may also influence its intracel- teins. Two general classes of proapoptotic family proteins exist: lular trafficking.83,86,87 ADAM17, ADAM10 and ADAM9 prodo- (1) those that share three homology regions (BH1, BH2 and mains are removed by a protein convertase (e.g., furin) in the BH3), which are termed multidomain proteins; and (2) those secretory pathway. Curiously, ADAM8 and ADAM28 have been that share little sequence homology except for the conserved BH3 shown to undergo autocatalytic prodomain removal.88,89 In this domain, also termed “BH3-only” proteins.64-67 These multido- way, ADAM proteins involved in fertilization are expressed dur- main proteins are also known as the Bcl-2/Bax-family in honour ing spermatogenesis as a full length form, and are not processed of Bax (Bcl-2 antagonist X), the first Bcl-2 antagonist discovered until the spermatozoa has reached the epididymis. There, they by Korsmeyer. Other members of this group are Bcl-2 antago- undergo removal of the prodomain and the metalloprotease nist/killer (Bak) and Bcl-2 ovarian killer (BOK).68,69 Among the domain, which suggests that they do not function as sheddases “BH3-only” group, we can find Bcl2 antagonist of cell death during spermatogenesis, sperm maturation and/or fertiliza- (BAD) and p53 upstream modulator (PUMA).70 It appears that tion.90-92 This is in striking contrast to ADAM17 or ADAM10, the pro-apoptotic family members Bax and Bak are crucial for which show prodomain processing during spermatogenesis and the induction of permeabilization of the outer mitochondrial their activity is important for inducing germ cell apoptosis.93 On membrane (OMM) and the subsequent release of apoptogenic the other hand, the disintegrin and cysteine-rich domains exhibit molecules, such as cytochrome c and DIABLO (also known as adhesive properties in different tissues, and the important role of SMAC), which leads to caspase-9 activation.32,71 proteolytically inactive ADAMs in reproductive organs (such as Evidence suggesting the involvement of the intrinsic path- ADAM2, 3, 12 and 23) suggest a relevant role of these adhesive way during physiological apoptosis comes from studies show- properties in biological process such as fertilization. Studies from ing upregulation of Bcl-2 proapoptotic proteins and activation ADAM knockout mice have indicated that ADAM 8, 9, 12 and of caspase-9. These data are reinforced by findings showing that 15 are dispensable for normal development.84,94,95 However, these ablation of apoptotic genes (Bax, Bim or Bik) or overexpression of results do not counteract the idea that they may have a function anti-apoptotic genes (such as Bcl-2) are associated with infertility in cell responses against external insults or pathological condi- due to the arrest of spermatogenesis at the onset of meiosis.5,32,71-76 tions. In particular, ablation of ADAM8, 9, 12 and 15 genes do In addition to physiological apoptosis, evidence suggesting the not have any overt consequences in testis development and male involvement of the intrinsic apoptosis pathway has been shown fertility. On the contrary, ablation of ADAM10, 17 and 19 shows after testicular heat stress,61 exposure to environmental toxicants that they have essential roles during development, particularly such as bisphenol A77 or diethyl maleate,78 autoimmune orchi- during heart differentiation.96,97 In the next section, we will sum- tis79 and streptozotocin-induced diabetes.80 Therefore, there is marize the data concerning the localization and putative function clear evidence that apoptosis and not other cell death forms (i.e., (in some cases) of ADAM proteins in the male reproductive tract. necrosis or autophagy) play a major role in germ cell demise. ADAM metalloproteases in fertilization. ADAM metalloproteases deserve special attention in mammalian fertilization. ADAM Metalloproteases At the cellular level, at least three steps are required to accom- plish fertilization: (1) sperm adhesion to the egg zona pellucida; The family of metalloproteinases known as metalloproteases and (2) sperm adhesion to the egg plasma membrane; and (3) sperm- disintegrins (ADAMs) has a central role in juxta/paracrine and egg fusion.98-103 autocrine signaling by controlling the ectodomain shedding of Three ADAMs has been described to have an important role different ligands and receptors.81 A typical ADAM consists of in fertilization: fertilin, a heterodimer formed by the subunits an N-terminal signal peptide, followed by a prodomain, a metal- fertilin-α (ADAM1) and fertilin-β (ADAM2), and cyritestin loprotease domain, a disintegrin domain, a cysteine-rich region, (ADAM3). However, these are not unique molecules that act an EGF-like domain, a transmembrane region and a cytoplas- to promote sperm and egg membrane fusion, because mice with mic domain. Interestingly, only about 60% of ADAMs contain sperm lacking ADAM1 and ADAM2 display normal in vitro

www.landesbioscience.com Spermatogenesis 197 fertilization.104 ADAM1, ADAM2 and ADAM3 proteins are organs, such as the prostate, the vas deferens and the seminal ves- expressed in the spermatozoa of different mammals.105 In par- icle, suggesting they may also play a role in the development and/ ticular, ADAM1 and ADAM2 are located in the posterior head or physiology of those tissues. In addition, the mammalian tes- of spermatozoa when they pass through the epididymis,106 and tis expresses other isoforms (i.e., ADAM10 or ADAM17) which ADAM3 is located in the acrosomal domain of spermatids and have some important roles during spermatogenesis. mature sperm.92,107 ADAMs 1–3 are synthesized as precursors Localization and distribution of ADAM proteins in the and then the pro- and metalloprotease domains are proteolyti- male reproductive tract. Localization of ADAM proteins in the cally removed during epididymal maturation, so mature ADAMs testis. So far, many ADAM proteins have been described as being have their disintegrin domain at the N-terminal.106,107 expressed in the testis, and a major group of them (ADAMs 2, Previous knockout mouse studies of ADAMs 1A, 1B, 2 and 3 3, 5, 6, 21, 24, 25, 26, 29 and 30) are exclusively detected in showed that male mice with deletions in the genes for Adam1a, this organ, as evaluated by RT-PCR (Figs. 2, 3 and Table 1). Adam2 or Adam3 are infertile due to sperm which are defective In this regard, ADAM1 and ADAM2 (also called fertilin-α and during the fertilization process.104,108 When ADAM1a, which is fertilin-β, respectively) were first discovered as a heterodimer on ER specific and not found in mature sperm, was knocked out, the sperm surface.115,116 They are found only in germ cells and their ADAM2 remained intact, but the sperm lost surface expression expression is developmentally regulated during spermatogen- of ADAM3 and ZP-binding ability.109 This result clearly indi- esis.117,118 ADAM3 is found in mammalian sperm and its mRNA cates that ADAM1b/ADAM2 (i.e., fertilin) is not essential for is expressed in primary spermatocytes (pachytene and diplotene), fertilization, at least in mice. ADAM24 may also play a role in secondary spermatocytes and in spermatids,92,109,117,119,120 but not fertilization because spermatozoa deficient in this protein show in a Sertoli cell line (15P-1), which suggests that ADAM3 is only reduced fertility and many polyspermic embryos.110 The available expressed in germ cells. ADAM5 mRNA is expressed in mouse evidence suggests that ADAM3 is a good candidate for sperm- testes in spermatocytes and spermatids (Fig. 3). In the testis, egg interactions, at least in mice, since in humans it has been ADAM5 protein localizes at the sperm surface as a precursor identified only as a pseudogene, suggesting that genes other than which is processed during epididymal maturation.121 ADAM5 ADAM3 must be involved in this process.111 Therefore, the avail- protein levels, similar to ADAM7 levels, are reduced in ADAM2 able data suggest that a complex interaction between ADAM1a, and ADAM3 null sperm. So, ADAM5 and ADAM7 expression ADAM1b and ADAM3 (and probably other proteins), rather depend upon ADAM2 and ADAM3 expression.121 than unique molecules, is required to achieve proper fertilization. mRNAs of ADAMs genes have been detected in testes of dif- Knockout studies in mice have provided evidence of the com- ferent species6, 20, 27, 29–31, 33 either in germ or Sertoli cells, and in plicated relationship among the ADAM1A, ADAM1B, ADAM2 some cases the expression pattern is available (ADAM24, 25, 26 and ADAM3 proteins. ADAM1 is absent and ADAM2 is dra- and 34), but there is a lack of studies showing their function matically reduced in Adam3-null mice.105 ADAM4 and ADAM6 in spermatogenesis and/or fertilization (Fig. 3 and Table 1). are dramatically reduced in Adam2 and Adam3 knockout sperm, ADAM19 is transiently expressed in the seminiferous cords of and premature processing of ADAM4 has been detected in mouse testes as shown by immunohistochemistry and RT-PCR ADAM3-null mice.90 In addition, it has been shown the pres- from 15.5–19.5 days post-coitus to two-day old animals.122 ence of different macromolecular complexes between ADAM1A/ Interestingly, it seems that ADAM19 mRNA levels are reduced ADAM2, ADAM1B/ADAM2 and ADAM2/ADAM3, as well as by follicle stimulating hormone (FSH) in a time-dependent man- ADAM6/ADAM2 and ADAM6/ADAM3 in testes and mature ner.122 ADAM32 is principally expressed in mouse testes and sperm. Moreover, during epididymal transit, ADAM7 is associ- epididymis. Its expression has been found during the meiotic ated with membranous vesicles (epididymosomes). This protein prophase and in pachytene spermatocytes as a precursor protein. is transferred to the sperm surface during epididymal transit in In the epididymis, ADAM32 is processed and localized at the mouse and human, and is subsequently expressed on the entire sperm surface.112,117,121 Since ADAM32 is highly homologous to head of acrosome-intact sperm and acrosome-reacted sperma- ADAM2 and ADAM3, it has a possible role in spermatogenesis tozoa.112,113 In this way, ADAM7 becomes an integral plasma and/or fertilization. Evidence for ADAM4, 6, 21, 24–27, 29, and membrane protein in sperm. Moreover, ADAM7 forms a com- 30 expression in Sertoli cells has been found in studies where plex with calnexin, heat shock protein 5 and integral membrane these proteins have been detected in the Sertoli cell-derived cell protein 2B in lipid rafts during sperm capacitation.114 Thus, there line 15P-1.117 is a complex interaction between the different ADAM proteins in According to the experimental biochemical data, most of the mammalian spermatozoa and, so far, their precise roles in sperm ADAMs expressed in the testis are proteolytically inactive, since maturation, capacitation and fertilization are still not fully under- the prodomain and the metalloprotease domain are removed stood. ADAM24 is located as a monomer in the equatorial region during epididymal transit. However, ADAM10, ADAM15 and of the sperm surface in mouse.110 When the sperm pass through ADAM17 are the only three ADAMs detected as precursors and the epididymis, ADAM24 located on the sperm membrane is in their catalytically active forms without the prodomain.93,123 We processed by removing the pre-domain.110 Thus, it is clear that have proposed that catalytically active ADAM10 and ADAM17 ADAM proteins play a major role in fertilization, but this is not could play a role in germ cell apoptosis (see below), but the role the only activity performed by these proteases in reproduction. of active ADAM15 remains unknown. In fact, ADAM proteins are also present in other reproductive

198 Spermatogenesis Volume 1 Issue 3 Figure 2. Schematic representation of ADAM metalloprotease distribution in the male reproductive tract. The figure shows a representation of the male reproductive tract; the boxes indicate the ADAM metalloproteases expressed in the respective organs.

Epididymis and vas deferens. Six ADAMs (4, 11, 15, 17, 23 These observations suggest that the transfer of ADAM7 to and 31) have been detected in the vas deferens of mouse, rat, epididymal spermatozoa, and the expression dependence of and human by RT-PCR (Table 1 and Fig. 2). The specific tis- ADAM5 and ADAM7 on the expression of ADAM2, ADAM3 sue localization and regulation of these ADAM proteins dur- and probably the other ADAMs expressed in the epididymis, ing development or pathological conditions have not yet been could be related to the acquisition of the fertilization capability explored. of sperm during maturation (Fig. 2). The Adam7 gene is expressed in human, rat and monkey epi- Prostate. ADAM9 has been detected in human prostate can- didymis, with higher levels in the proximal caput than in the cer, and its mRNA and protein levels are significantly upregu- distal regions.112,113,124-127 At least in mouse and rat, its mRNA is lated under these conditions compared to normal tissue.128,129 found exclusively in the epididymis, and its expression strongly Moreover, mouse prostate cancer in the context of an ADAM9 relies upon androgen levels.113,124 As stated above, ADAM7 is deficiency shows a well-differentiated tumour, whereas littermate detected in the principal cells of the epididymis and is trans- controls expressing wild type ADAM9 had predominantly poorly ferred to the spermatozoa. Biochemical studies have shown that differentiated, and in some cases significantly larger, tumours. no processing or modification of ADAM7 occurs in the epi- Gain-of-function experiments have shown that ADAM9 overex- didymis, and this protein is found at the cell surface in mature pression induces epithelial hyperplasia, and later leads to pros- spermatozoa. ADAM28 is expressed in mouse and rat almost tatic intraepithelial neoplasia lesions.130,131 Interestingly ADAM9 88,112 exclusively in the caput of the epididymis. Testicular factors has been found to bind integrin αvβ5 which suggest that this pro- rather than androgens are required for ADAM28 gene expres- tein could have functions related to cell adhesion and migration sion, since in gonadectomized mice, ADAM28 expression dis- during prostate development and/or cancer.132 appeared; after castration, ADAM28 levels did not fully recover ADAM15 at the mRNA and protein levels is significantly after treatment with dihydrotestosterone.112,124 Other ADAM overexpressed in multiple types of adenocarcinoma, specifically proteins such as ADAM15, ADAM23, ADAM31 and ADAM32 during the metastatic progression of human prostate and breast have been found to be expressed, but not exclusively, in mouse cancer.133,134 Knockdown of ADAM15 decreases cell migration epididymis, but their function and subcellular localization are and adhesion of PC3 cells (an androgen-independent prostate unknown. cancer cell line) to specific extracellular matrix proteins, as well as

www.landesbioscience.com Spermatogenesis 199 Figure 3. Schematic representation of ADAM metalloprotease distribution in the seminiferous epithelium. The cartoon depicts a representation of the seminiferous epithelium, and the boxes indicate the ADAM metalloproteases expressed in different cell types. The figure shows ADAM metalloproteases with a specific cell type distribution; other ADAMs distributed throughout all cell types (e.g., ADAM10 or ADAM17) are not depicted in this scheme. the cleavage of N-cadherin.134 This experimental evidence is con- is a 145 kDa glycosylated transmembrane protein, which upon sistent with the ability of ADAM15 to bind α5β1 and αvβ3 inte- binding to its ligand (SCF), initiates a signaling cascade lead- grins.135,136 This experimental evidence suggests that ADAM15 ing to proliferation, differentiation, migration and survival.139-141 may play a role in prostate tumour cell interactions and in the In studies with cultured stem cells derived from mastocytes and metastatic progression of human prostate cancer.134 umbilical cord endothelial cells, release of the c-kit ectodomain has been found to be dependent on TACE/ADAM17 activity.140 ADAM10 and ADAM17 as Inducers Moreover, embryonic cells have shown a significant increase of Germ Cell Apoptosis: A Working Model in apoptosis after being incubated with PMA, a phorbol ester known to activate PKC, but not in cells expressing a catalyti- ADAM10 and ADAM17 are two widely expressed metallopro- cally inactive mutant of TACE/ADAM17. This result suggests teases linked to the ectodomain release of not only ligands, but a strong link between TACE/ADAM17, processing of the c-kit also receptors such as Notch, epidermal growth factor (EGFR), ectodomain and activation of apoptosis. Our own data shows the p75 neurotrophin receptor (p75NTR), and c-kit.81,84,85 Despite that in vivo PMA induces apoptosis in germ cells from 21-day the fact that ADAM1 was the first member of the ADAM family old rats, which was prevented when a pharmacological inhibitor discovered in the testis, it was not until five years later that TACE of ADAM17 was present at the time of PMA administration.93 (tumor necrosis factor-α converting enzyme) was recognized as ADAM17, but not ADAM10, is upregulated in germ cells under- a member of the metalloprotease family.137 Since then, TACE/ going physiological apoptosis and pharmacological inhibitors of ADAM17 has been established as a key protease in mammalian ADAM17 are able to significantly prevent physiological apop- development. Several studies have shown that the receptor tyro- tosis. Overall, these results uncover a new a role for ADAM17 sine kinase c-kit is a substrate of ADAM17.138 The c-kit receptor as a key physiological regulator of germ cell apoptosis during

200 Spermatogenesis Volume 1 Issue 3 Table 1. Distribution of ADAM metalloproteases in reproductive male tract ADAM Alternative name Localization Organism Reference Fertilinα Testes Mus musculus 120 ADAM1 PH-30α Prostate Rattus norvegicus 125

Fertilinβ ADAM2 Testes Mus musculus 120 PH-30β

Cyritestin ADAM3 Testes Mus musculus 108, 117, 120 tMDC I Testes Mus musculus 117, 120 Vas deferens ADAM4 tMDC V 112 Testes Rattus norvegicus 125 Prostate

Testes Mus musculus 120 ADAM5 tMDC II Testes Macaca fascicularis 170 Testes Rattus norvegicus 125

Testes Mus musculus 117 Testes Macaca fascicularis 170 ADAM6 tMDC IV Prostate Testes Rattus norvegicus 125 Epididymis Homo sapiens 126 Epididymis Rattus norvegicus 112, 127 Sperm maturation-related glycoprotein GP-83 ADAM7 Epididymis Macaca fascicularis 127 EAP I Epididymis Mus musculus 112, 124 Epididymal Sperm 113

MS2 ADAM8 CD156a Prostate Homo sapiens 129 Macrophage cysteine-rich glycoprotein

Cellular disintegrin-related protein Testes Mus musculus 171 Meltrin-gamma Testes Homo sapiens 171 ADAM9 Myeloma cell metalloproteinase Prostate 128, 171, 172 MDC9 Testes Rattus norvegicus 157

CDw156 Kuzbanian protein homolog Testes Rattus norvegicus 157 ADAM10 CD156c Myelin-associated metalloproteinase Prostate Homo sapiens 172, 173 MADM

Vas deferens 112 ADAM11 MDC Mus musculus Testes 174 ADAM12 Meltrin-alpha Prostate cancer Mus musculus 175 Metalloprotease RGD disintegrin protein Prostate Homo sapiens 133, 134 MDC-15 Testes Mus musculus 123 ADAM15 Metargidin Epididymis 112 AD56 Vas deferens CRII-7

TNFalpha-converting enzyme Testes Rattus norvegicus 93, 157 ADAM17 (TACE) Vas deferens 112 CD156b Prostate Homo sapiens 172

Testes Rattus norvegicus 125 ADAM18 tMDC III Testes Macaca fascicularis 170 Testes Homo sapiens 176

Meltrin-beta ADAM19 MADDAM Testes Mus musculus 122 FKSG34 protein

ADAM20 Testes Homo sapiens 177

www.landesbioscience.com Spermatogenesis 201 Table 1. Distribution of ADAM metalloproteases in reproductive male tract (continued)

ADAM Alternative name Localization Organism Reference

Mus musculus 117, 178 ADAM21 ADAM31 Testes Homo sapiens 177 ADAM22 Testes Mus musculus 174 ADAM23 MDC-3 Epididymis Mus musculus 112 MDC-L Vas deferens ADAM28 Epididymis Macaca fascicularis 179

ADAM24 Testase1 Testes Mus musculus 110, 117, 180 ADAM25 Testase2α and Testase2β Testes Mus musculus 117, 180, 181 ADAM26 Testase3 Testes Mus musculus 117, 180 tMDC III ADAM27 Testes Mus musculus 180 ADAM18

TECADAM Epididymis Mus musculus 88, 112, 124 eMDC II ADAM28 MDC-Lm MDC-Ls ADAM23 Epididymis Rattus norvegicus 112

Testes Mus musculus 117 ADAM29 CT73 Testes Homo sapiens 182

Testes Mus musculus 117 ADAM30 Testes Homo sapiens 182

Testes, ADAM31 ADAM21 Epididymis Mus musculus 183 Vas deferens

Testes ADAM32 Mus musculus 104, 112, 117 Epididymis

Testes Mus musculus 184 ADAM33 Prostate Homo sapiens 185 ADAM34 Testase4 Testes Mus musculus 186 ADAM36 Testase6 Testes? Mus musculus 187 ADAM37 Testase7 Testes? Mus musculus 187 ADAM38 Testase8 Testes? Mus musculus 187 ADAM39 Testase9 Testes? Mus musculus 187 ADAM40 Testase10 Testes? Mus musculus 187 mammalian spermatogenesis. These data raise several questions of proapoptotic signals such as p53 and/or p73. The central role such as: Which is/are the physiological substrate(s) shed by of c-kit in germ cell apoptosis comes from studies showing that ADAM17 during germ cell apoptosis? How is ADAM17 acti- blocking the binding of c-kit to its ligand (SCF) in Sertoli cells vated under physiological conditions? Does ADAM17 participate induces apoptosis.142 In addition, an inactivating point muta- in non-physiological germ cell apoptosis (induced by heat stress tion at the intracellular domain of c-kit, which blocks binding of or genotoxins)? Is ADAM17 involved in germ cell apoptosis phosphoinositide-3-phosphate kinase (PI3K), induces apoptosis under pathological conditions? of germ cells and infertility.75,142,143 Moreover, genetic evidence Here we would like to propose a model of germ cell apop- in the mouse testis suggests that inactivation of c-kit signaling tosis where shedding of the extracellular domain of c-kit by is linked to apoptosis mediated by the expression of Fas.144 In ADAM17 leads to germ cell apoptosis (Fig. 4). This proposal is humans, associations between polymorphisms in the KIT gene based on our experimental evidence that germ cells undergoing and idiopathic infertility have also been found.145 Thus, inacti- physiological apoptosis lack the extracellular domain of c-kit.93 vation of c-kit seems to promote apoptosis of mammalian germ We propose that this event will turn off survival signaling, such cells during spermatogenesis, and probably leads to male infertil- as the PI3K/Akt pathway, which in turn will trigger activation ity. Even though c-kit is a good candidate as the physiological

202 Spermatogenesis Volume 1 Issue 3 Figure 4. A schematic drawing illustrating an emerging mechanism of action of ADAM metalloproteases in germ cell apoptosis. Active ADAMs metalloproteases cleave specific substrates at the cell surface of germ cells (ADAM17) or Sertoli cells (ADAM10). In this model, the activation of ADAM10 at the surface of the Sertoli cell would have a pro-survival effect by decreasing the half-life of FasL. On the other hand, activation of ADAM17 in the germ cell (spermatocytes and/or spermatogonia) would be by oxidative damage and/or DNA damage. Both insults would converge, activating the tyrosine kinase c-Abl, which in turn would activate p38 MAPK and/or PKC, promoting activation of ADAM17 and probably its transit to the cell surface. Thus, apoptosis induction is due to the inhibition of survival signals (extracellular c-kit domain shedding) and the induction of apoptotic signals (Fas receptor activation). substrate of ADAM17, we cannot rule out that other survival TAp73 isoforms can induce apoptosis, ΔNp73 isoforms act as receptors expressed by germ cells could also be processed by anti-apoptotic factors. p73 transcriptional activity is modulated ADAM17 during germ cell apoptosis. by the tyrosine kinase c-Abl and pharmacological inhibition of Following c-kit extracellular domain shedding by ADAM17, this enzyme with STI571 (STI) leads to the abolition of p73 we propose the stabilization/activation of p53 and/or p73, two activity.152-154 p53, p73 and c-Abl are expressed in germ cells, and well-known proteins involved in the transcriptional and post- we have shown that in vivo pharmacological inhibition of c-Abl transcriptional activation of many pro-apoptotic molecules.146-148 prevents germ cell apoptosis induced by etoposide exposure.152,155 The role of p53 has been extensively studied in germ cells and Our unpublished results show that STI prevents physiological in other apoptosis models. Even though experimental evidence apoptosis during the first wave of spermatogenesis, positioning has shown a role for p53 in physiological and genotoxin-induced p73 as a key transcriptional regulator of proapoptotic genes in apoptosis, mice lacking p53 show no major defects in spermato- germ cells (Codelia V, unpublished results). Moreover, p53 and genesis, which casts doubts on its central role during this pro- p73 are highly expressed in apoptotic germ cells, which places cess.24 Thus, there is a need to look for other related proteins these two master genes in a central position in the apoptotic which may fulfil the key role of p53 in apoptosis. p73 is a member initiation cascade (Fig. 4).47 As a complementary pathway, Fas of the p53 family which has been shown to have, like p53, the could be activated by binding to membrane-bound FasL, which ability to induce apoptosis in different cell types. p73 is a tran- is expressed by Sertoli cells (Fig. 4). Experimental evidence has scription factor which shares amino acid homology and structural shown that FasL could be processed by ADAM10, but not by similarity with p53, especially within its DNA binding domain. A DA M17.156 In this way, activation of ADAM10 could release Because of this, p73 share several target genes with p53 such as the extracellular domain of FasL and prevent its binding to Fas Bax, Puma and Fas.149,150 p73 is expressed in several isoforms, by in germ cells. This proposal came from experiments showing that alternative use of its promoter, generating TAp73, which contains only membrane-bound but not soluble FasL can induce apopto- the transactivation domain, or ΔNp73, which does not contain sis. Thus, caspase activation in germ cells will be the consequence the transactivation domain.146,151 It has been show that, while the of the combined action of the intrinsic and extrinsic pathways.

www.landesbioscience.com Spermatogenesis 203 Figure 5. Pharmacological inhibition of p38MAPK prevents physiological and etoposide-induced germ cell apoptosis. (A) During the first round of spermatogenesis a maximum rate of germ cell apoptosis is observed in 25-day old rats (Control). In order to evaluate the role of p38 MAPK, different concentration of a pharmacological inhibitor (PD169316) were injected in the testes of 24-day-old rats and evaluated apoptosis 24 h after, when rats were 25 days old. PD169316 decreases the rate of physiological germ cell apoptosis in a concentration dependent manner. A high concentration of this inhibitor is toxic to germ cells. (B) Etoposide (100 μM) induces a significant increase in germ cell apoptosis when it is administered intratesticularly in 21-day old rats. However, when etoposide is administered along with 5 μM PD169316 (PD), germ cell apoptosis decreases significantly as compared to etoposide alone. *p < 0.05 n = 3.

Prodomain processing and cell surface exposure are two It has been shown that c-Abl as well as p73 and p53 are acti- important events in ADAM activation. We have shown that, vated by oxidative stress and DNA damage.163 In germ cells, it upon exposure to etoposide (an inhibitor of toposisomerase-II), has been proposed that abnormal recombination in spermato- ADAM10 and ADAM17 are upregulated at the cell surface, cytes might be a major source of DNA damage, which could which correlates with germ cell apoptosis in 21-day old rats.157 activate c-Abl/p73 and/or p53. On the other hand, oxidative Interestingly, neither ADAM10 nor ADAM17 were upregulated stress has not been assessed directly in apoptotic germ cells, but in testes subjected to heat stress (41°C for 15 min).15,157 Moreover, its relevance is known in several pathological conditions and ADAM9, another metalloprotease involved in apoptosis after after environmental toxicant (e.g., xenoestrogens) exposure.164 oxidative stress, is not upregulated by etoposide or heat stress, Although merely speculative, we would like to propose that oxi- suggesting that upregulation of ADAM10 and ADAM17 is not a dative stress and/or DNA damage can be sensed in germ cells by general process for all cell surface proteins. ataxia-telangiectasia mutated (ATM) and DNA-PK, two tyro- It remains controversial as to whether or not the shedding sine kinases which phosphorylate and activate c-Abl in somatic activity of ADAM17 and/or ADAM10 is regulated exclusively by cells.165,166 In somatic cells, oxidative stress induces posttrans- prodomain release. In this way, p38 MAPK and protein kinase lational modifications and assembly of the DNA-PK complex C (PKC) (via PMA) phosphorylates the intracellular domain on DNA along with activation of ATM.167 Therefore, it is not of A DA M17.158,159 We have shown that after heat stress, p38 farfetched to propose that a similar mechanism may work in MAPK is activated in apoptotic germ cells,15 and our unpub- stressed germ cells (spermatocytes and spermatogonia), thereby lished data indicates that a pharmacological inhibitor of p38 inducing apoptosis. Our model may also apply to pathological MAPK (PD169316) prevents physiological germ cell apoptosis (e.g., varicocele) and environmental situations (e.g., occupational in a concentration-dependent manner (Fig. 5). Additionally, toxin exposure) where oxidative damage has been shown to be PD169316 prevents germ cell apoptosis induced by etoposide, an important contributor to inducing germ cell apoptosis.168,169 suggesting that p38 MAPK is involved both in physiological and Interestingly, the environmental toxicant mono-(2-ethylhexyl) genotoxicity-induced germ cell apoptosis. Interestingly, PKC and phthalate (MEHP) induces upregulation of matrix metallopro- p38 MAPK can be phosphorylated (activated) by c-Abl, the same teases, including ADAM17.62 Therefore, the model of germ cell tyrosine kinase that targets p73. This kinase is present in germ apoptosis proposed in this work may apply to many pathologi- cells and it has been shown to be highly expressed in primary cal conditions and environmental conditions experienced by the spermatocytes; c-Abl-null mice are infertile, showing a disruption mammalian testis (Fig. 1). in spermatogenesis.160-162 Thus, we propose that, in germ cells, c-Abl could activate p38 MAPK and PKC, which in turn will Concluding Remarks phosphorylate ADAM17 and trigger its activation, probably by promoting its translocation to the cell surface and/or prodomain It is well known the importance of some ADAMs in fertilization release (Fig. 4). At the cell surface, or during its transit to its final (e.g., ADAM1-3), and it seems that they do not have a major role localization, ADAM17 could induce shedding of the extracellu- during spermatogenesis since gene ablation studies have shown lar domain of survival receptors (e.g., c-kit), which in turn will no overt effects in testis histology. ADAMs have a complex gene induce apoptosis. expression pattern throughout the male reproductive tract and

204 Spermatogenesis Volume 1 Issue 3 some of them are expressed in specific organs (e.g., only in testis), apoptosis. This model may stimulate new ideas and research while others are found in different compartments (e.g., ADAM15 avenues in order to elucidate the role of ADAMs in germ cell in testis and prostate), suggesting that their function may change apoptosis, and probably the participation of other components in according to the cellular context. In this review we have highlight germ cell apoptosis. recent work showing that ADAM17 and ADAM10 are expressed in mammalian testes and they participate regulating physiologi- Acknowledgments cal and induced germ cell apoptosis. Our molecular model states Part of this work was financed by a FONDECYT grant (1110778) that both cell autonomous and para/juxtacrine signaling events to R.D.M. between germ-Sertoli cell are important in order to regulate

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208 Spermatogenesis Volume 1 Issue 3