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Aquaporin biology of spermatogenesis and sperm physiology in mammals and teleosts.

Abstract. Fluid homeostasis is recognized as a critical factor during the development, maturation, and function of vertebrate male germ cells. These processes have been associated with the presence of multiple members of the aquaporin superfamily of water and solute channels in different cell types along the reproductive tract as well as in spermatozoa. We present a comparative analysis of the existing knowledge of aquaporin biology in the male reproductive tissues of mammals and teleosts. Current data suggest that in both vertebrate groups, aquaporins may have similar functions during differentiation of spermatozoa in the germinal epithelium, in the concentration and maturation of sperm in the testicular ducts, and in the regulation of osmotically induced volume changes in ejaculated spermatozoa. Recent studies have also provided insight into the possible function of aquaporins beyond water transport, such as in signaling pathways during spermatogenesis or the sensing of cell swelling and mitochondrial peroxide transport in activated sperm. However, an understanding of the specific physiological functions of the various aquaporins during germ cell development and sperm motility, as well as the molecular mechanisms involved, remains elusive. Novel experimental approaches need to be developed to elucidate these processes and to dissect the regulatory intracellular pathways implicated, which will greatly help to uncover the molecular basis of sperm physiology and male fertility in vertebrates.

Introduction

Spermatogenesis is a major reproductive event in which mature male haploid gametes, termed spermatozoa, are formed in the testis. During this process, the germ line stem cells embedded in the supporting Sertoli cells of the seminiferous tubules divide mitotically to expand the pool of spermatogonia; after two meiotic divisions, these actions will give rise to spermatocytes and haploid spermatids. The spermatids subsequently undergo a morphological and molecular remodeling process, known as spermiogenesis, during which the head, middle piece, and flagellum of the spermatozoa differentiate (Eddy, 2006). In tetrapods, spermatozoa are released into the lumen of the seminiferous tubules and transported through the efferent ducts to the epididymis, from where they will be ejaculated into the female reproductive tract (Eddy, 2006). In piscine species, spermatozoa are also released into the tubular lumen, or can differentiate from free spermatocytes or mature spermatids in the lumen, and are subsequently directly ejaculated from the spermatic ducts to the external environment (Schulz et al., 2010).

In the mammalian testis, fluid homeostasis during spermatogenesis and sperm maturation is critical for male fertility (Huang et al., 2006). Water efflux from the Sertoli cells of the germinal epithelium and from germ cells controls the seminiferous tubule fluid to create a suitable environment for spermatogenesis (Russell et al., 1989; Rato et al., 2010). Fluid movement also occurs during the transformation of round spermatids into spermatozoa, which is accompanied by a drastic reduction of the cytoplasm and condensation of the chromatin (Eddy, 2006; Huang et al., 2006). Finally, control of the fluid composition of the lumen of the seminiferous tubules by Sertoli cells and by the efferent ducts and epididymis by epithelial cells is essential for the transport, maturation, and concentration of spermatozoa (Setchell et al., 1969; Hinton and Setchell, 1993; Hermo et al., 2004). In teleosts, testicular fluid transport presumably is also essential during spermatogenesis, and during hormone-induced hydration of the seminal fluid at spermiation, which may increase the interlobular pressure in the testis, thereby aiding in transport of the sperm through the seminiferous tubules while maintaining the correct osmolality of the seminal plasma (Coward et al., 2002).

In both mammalian and teleost spermatozoa, osmotic changes associated with water and ion fluxes are also vital for the activation of motility and subsequent natural fertilization (Cooper and Yeung, 2003; Cosson et al., 2008a, b). In mammals, physiological hypotonicity can facilitate the acrosome reaction in the sperm through calcium increase and acrosome swelling (Rossato et al., 1996; Zanetti and Mayorga, 2009); this hypotonic stress is required for the activation of sperm motility once released from the epididymis (Willoughby et al., 1996). Similarly, in freshwater (FW) and marine teleosts, activation of motility is, respectively, induced by the hypoor hyperosmotic aquatic environment into which the sperm are ejaculated (Morisawa and Suzuki, 1980; Cosson et al., 2008a).

Because of the importance of fluid transport and efficient cell volume regulation during germ cell development and sperm motility, the potential role of cellular membrane channels such as aquaporin water channels has received particular consideration. Studies in different mammalian species have now demonstrated the presence of classical, water-selective aquaporins as well as water and solute-permeable aquaporins, also known as aquaglyceroporins in the male reproductive tract and spermatozoa (Huang et al., 2006; Carbrey and Agre, 2009; Yeung et al., 2010; Yeung, 2010). However, the specific physiological roles of most of these channels during spermatogenesis and sperm physiology are yet not well understood. Recently, the distribution of multiple aquaporins in the testis of teleosts, which harbor a large repertoire of functionally conserved aquaporin paralogs as a result of teleost-specific gene duplications (Tingaud-Sequeira et al., 2010; Cerda and Finn, 2010; Finn et al., 2014), has also been investigated. Recent studies on one of these species, the marine teleost gilthead seabream (Sparus aurata), have revealed a complex pattern of aquaporin expression in germ cells and ejaculated spermatozoa that is strikingly similar to that reported in mammals. In this review, we present a comparative view of the current knowledge of aquaporin expression, regulation, and function of the mammalian and teleost male reproductive tracts, including recent data that are starting to uncover the role of some aquaporins during sperm physiology.

Functional Organization and Endocrine Control of Spermatogenesis

In vertebrates, the testis is composed of two major compartments, the seminiferous tubules and the interstitium, which are separated by a basal membrane, a layer of collagen, and the peritubular cells (myofibroblasts) (Weinbauer et al., 2010). The basal membrane together with the Sertoli cells, which delimit the seminiferous tubule, comprise the blood-testis barrier (Weinbauer et al., 2010). Sertoli cells provide the structural support for the developing germ cells within the seminiferous epithelium (Mruk and Cheng, 2004), and allow the contractility necessary for release of the immotile testicular sperm into the efferent duct (Wistuba et al., 2007). In the interstitial compartment, the Leydig cells surrounding the blood vessels are the main source of sex steroids such as androgens (Weinbauer et al., 2010).

Spermatogenesis and spermiogenesis are complex and precise processes encompassing the respective division and differentiation of germ cells. The primary type A diploid spermatogonia lie at the base of the seminiferous tubules, where they can either renew themselves and/or differentiate into type B spermatogonia (Phillips et al., 2010). Type B spermatogonia then give rise to spermatocytes that progress into meiosis to form haploid round spermatids, which transcribe high levels of messenger ribonucleic acids (mRNAs) that are not translated until spermiogenesis (O'Donnell et al., 2006). During spermiogenesis, mature round spermatids transform into spermatozoa, which, in mammals, sequentially includes formation of the acrosome from the Golgi apparatus, elongation of the spermatids, and condensation of the nucleus, which becomes transcriptionally arrested as histones are replaced by protamines (Weinbauer et al., 2010). Elongation of the spermatids continues until the flagellum is fully formed, which is concomitant with extrusion of most of the cell cytoplasm, the so-called residual body, which is phagocytosed by the Sertoli cell (Weinbauer et al., 2010). At spermiation, differentiated spermatozoa are released into the tubular lumen and transported through the efferent ducts to the epididymis, where sperm concentrates and matures (Hess, 2002; Robaire et al., 2006).

In teleost fish, the major events of spermatogenesis are similar to those of mammals. However, in these species germ cell development is clonal, since each spermatogonium is surrounded by a single Sertoli cell in the seminiferous lobules; and thus a group of clonal germ cells arising from a single spermatogonium develops synchronously within the cyst (Schulz et al., 2010). Moreover, during spermatogonial mitosis, cytokinesis is incomplete, leaving the spermatogonial clonal cells interconnected by cytoplasmic bridges (Schulz et al., 2010). Spermiogenesis in fish is similar to that of mammals except that spermatozoa can differentiate from haploid germ cells released into the tubular lumen and do not develop a proper acrosome (Lahnsteiner and Patzner, 2008; Schulz et al., 2010). In addition, because the teleost testis lacks a real epididymis, the processes of storage, nutrition, and resorption of spermatozoa, as well as regulation of the composition of the seminal fluid, occur along the efferent duct (Lahnsteiner, 2003).

In both mammals and teleosts, germ cell development and spermiogenesis are tightly regulated by the pituitary glycoprotein follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (Holdcraft and Braun, 2004; Levavi-Sivan et al., 2010). In mammals, FSH binds specifically to its cognate receptor in Sertoli cells to control the production of nutritional and regulatory factors for germ cells, whereas LH acts through the LH/choriogonadotropin receptor in Leydig cells to stimulate androgen secretion (Holdcraft and Braun, 2004; Schlatt and Ehmcke, 2014). In teleosts, however, although the functions are similar to their mammalian counterparts, both are potent steroidogenic hormones acting through expression of the two receptors in Leydig cells (Schulz et al., 2010; Levavi-Sivan et al., 2010; Sambroni et al., 2013; Chauvigne et al., 2012, 2014).

Activation of the Leydig cells results in the production of testosterone and 11-ketotestosterone (11-KT), which are, respectively, the major androgens in the mammalian and teleost testis (Borg, 1994; Walker, 2011). These androgens are responsible for initiation and maintenance of spermatogenesis through activation of androgen receptors expressed in Sertoli cells, and possibly also in Leydig and germ cells of teleosts (Miura et al., 1991; Ikeuchi et al., 2001; Walker, 2011; Chauvigne et al., 2014). Estrogens, produced from testosterone by the aromatase enzyme in Leydig and germ cells and found at high concentrations in the seminal fluid, also play a role in the mammalian efferent ducts and epididymis (Hess and Carnes, 2004); in contrast, in teleosts, estrogens seem to control renewal and proliferation of spermatogonia (Amer et al., 2001; Kobayashi et al., 2011). Finally, progesterone is also needed for proper Sertoli cell function, spermiogenesis, and testosterone biosynthesis in mammals (Han et al., 2009), whereas piscine-specific progestins control meiosis initiation, spermiation, and milt production in teleosts (Miura et al., 2006; Scott et al., 2010; Chen et al., 2013).

Aquaporin Localization and Function in the Reproductive Tract

Mammalian testis

Cellular localization of aquaporins in the testis of mammals has been investigated in a number of species, using immunocytochemical approaches (Table 1). These studies have revealed the presence of most of the aquaporin paralogs, including the water-selective aquaporins AQPO, -1,-2, -4, and -5; AQP8; the aquaglyceroporins AQP3, -7, -9, and -10; and the unorthodox AQP11, which is an intracellular, water-permeable channel (Ikeda et al., 2011; Yakata et al., 2011; Ishibashi et al., 2014). For some aquaporins, speciesspecific expression has been reported, although in these cases the identities of aquaporins have not been validated at the mRNA level, or subcellular localization of the protein products has not been investigated, and therefore differences among species may be related to the lack of specificity of the antibodies employed.

In the rat and stallion testis, interstitial Leydig cells express AQPO (Table 1), whereas AQP2 and -5 have also been detected in stallion Leydig cells. In the murine and feline testis, some interstitial cells, not specifically characterized as Leydig cells, express AQP1, although this was not the case for other mammals. Nevertheless, the presence of water-selective aquaporins in Leydig cells may indicate the requirement of these channels for water homeostasis in these steroidogenic cells (Hermo et al., 2004). The Leydig cells of most mammals studied, except the bat and dog, also express the aquaglyceroporin AQP9, suggesting that this channel could also allow the passage of solutes across these cells. In rat Sertoli cells, immunolocalization studies have shown the presence of AQP0, -4, and -8, the latter also being found in human but not in mouse. In rat, the synthesis of AQP0 and -8 in Sertoli cells seems to be differentially regulated during spermatogenesis, while AQP8 is present in all phases of the spermatogenic cycle (Calamita et al., 2001a; Badran and Hermo 2002), AQP0 is strongly upregulated in tubules at the round spermatid stage (Hermo et al., 2004). Interestingly, AQP0 and -4 have been suggested to mediate membrane junctions (Engel et al., 2008; Kumari and Varadaraj, 2009), and therefore these channels might contribute to cell adhesion structures in Sertoli cells that are part of the testis-blood barrier that is formed at this stage (Russell et al., 1989). The redundant expression of AQP0, -4, and -8 in Sertoli cells, as well as of AQP9, as shown in human and rat, could also suggest a role of the various channels in the movement of water and solutes through the seminiferous epithelium into the lumen (Rato et al., 2010). In rat Sertoli cells, AQP4 and -9 interact with the [Cl.sup.-]/HC[O.sub.3.sup.-] transporter cystic fibrosis transmembrane conductance regulator (CFTR) (Jesus et al., 2014a, b); and it is believed that this interaction contributes to the control of the seminiferous tubular secretion, as is suggested to occur in the epididymis (see Mammalian efferent ducts and epididymis below).

Germ cells of most mammalian species express AQP7 and -8, although in the stallion spermatids AQP0 and -2 have been detected, and AQP1 has been found in bat spermatids (Table 1). In human, mouse, and rat, different studies reported that AQP8 immunolabeling is present in all germ cells, whereas AQP7 is restricted to round and elongating spermatids and in rat residual bodies. However, AQP7 has also been found in rat spermatocytes. In rodents, expression of the intracellular AQP11 in the caudal cytoplasm of elongated spermatids and in the residual bodies just before spermiation is also well conserved. Germ cells also express AQP9, although the expression of this channel appears to be more variable. In humans, it is found in primary spermatocytes and maturing spermatids, but only in spermatocytes in the rat, and exclusively in spermatids in stallion.

The presence of AQP8, -9, and -11 in the plasma membrame of late germ cells, and particularly of AQP7, which is up-regulated specifically in spermatids, suggests that these channels might be involved in mediating the water loss and cytoplasmic condensation that occurs during spermatozoa differentiation (Suzuki-Toyota et al., 1999; Calamita et al., 2001a, b; Yeung et al., 2009a, 2010; Sohara et al., 2009). For AQP11, it has recently been shown that siRNA-mediated AQP11 knockdown in the hamster testis affects the expression of genes involved in spermatogenesis and androgen production, suggesting a role for this intracellular channel in the coordinated regulation of signaling pathways during testis development (Shannonhouse et al., 2014). However, the functions and mechanisms of action of these aquaporins during spermatogenesis still remain poorly understood because AQP7- or AQP8-deficient mouse models are fertile and show no evident phenotype (Yang et al., 2005; Sohara et al., 2007). AQP11-knockout models also do not clarify the role of AQP 11 in the testis, because animals die of renal failure before puberty, by postnatal day 60, with cysts forming in their renal cortices and large vacuoles of endoplasmic reticulum origin forming in proximal tubule cells (Morishita et al., 2005). Although it might be necessary to investigate in more detail the testicular and sperm phenotypes of these transgenic models, these observations, and the fact that redundant expression of aquaporin paralogs occurs in both somatic and germ cells of the testis, suggest that aquaporins might compensate for each other in these cells (Suzuki-Toyota et al., 2010). Therefore, to avoid potential genetic compensation mechanisms, other approaches aimed at affecting aquaporin function and/or trafficking at the protein level in the cell are necessary to elucidate the role of aquaporins during spermatogenesis.

Mammalian efferent ducts and epididymis

The efferent ducts are the major sites of water reabsorption (up to 90%) entering the lumen from the seminiferous tubules (Clulow et al., 1998). This water loss would serve to concentrate the sperm, allowing interactions of the sperm surface with the secretory products of the epididymal epithelial cells needed for sperm maturation. Disruption of this process leads to an abnormal luminal environment resulting in a decrease in sperm maturation and concentration, and the loss of fertility (Clulow et al., 1998; Hess, 2002).

Anatomically, the epithelium of the efferent ducts is classified as pseudostratified columnar and is composed of ciliated, nonciliated, and basal cells (Hess, 2002). In many mammals, AQP1 is present in the apical microvilli, basolateral plasma membranes, and apical endosomes of the nonciliated cells and the cilia of ciliated cells of the efferent duct epithelia (Table 1). AQP1 is also expressed in the apical membrane of endothelial cells, where it might mediate removal of water from the intertubular space of the efferent ducts to the vasculature (Badran and Hermo, 2002). AQP9 and AQP10 are present in the microvilli of nonciliated and ciliated cells, whereas AQP7 and -11 are also found in the rat. The presence of different classical aquaporins and aquaglyceroporins in the efferent duct epithelia suggest that these channels may be involved in the rapid movement of both water and solutes between the lumen and the efferent duct cells (Hermo et al., 2004; Hermo and Smith, 2011). One of these solutes may be glycerol, which has been proposed as a metabolic substrate for sperm and thus could contribute to sperm maturation (Da Silva et al., 2006a, b). The role of aquaporins in these processes is supported by the finding that estrogens and androgens can regulate the expression of AQP1 and/or -9 in the rat efferent duct epithelia (Fisher et al., 1998; Pastor-Soler et al., 2002, 2010; Oliveira et al., 2005). Accordingly, mice deficient in estrogen receptor alpha show a dramatic reduction of AQP1 and -9 immunoreaction in the efferent ductules and impaired water reabsorption, which leads to water accumulation in the testis and a decrease in sperm concentration and motility (Ruz et al., 2006). However, the role of AQP10 in the rat efferent ducts remains unknown, although it is possible that its function is redundant to that of AQP9.

In mammals, the efferent ducts are connected to the epididymis, a highly coiled tube where 55%-65% of total sperm is stored (Turner, 1995; Robaire et al., 2006). The epididymis is divided into three main regions; the initial segment or head (caput), which receives spermatozoa via the efferent ducts, the body (corpus), and the tail (cauda), which is involved in fluid absorption to concentrate the sperm. The epididymal epithelium consists of different cell types, narrow/apical cells, clear cells, principal and basal cells, and lymphocytes and monocytes/macrophages, termed halo cells, which are present in one, several, or all regions of the epithelium, respectively (Robaire et al., 2006). Nonfunctional spermatozoa mature during their migration from the proximal to the distal epididymis to acquire their motile and fertile properties (Cornwall and Horsten, 2007). This process involves modifications in composition of the flagellum plasma membrane (Dacheux and Dacheux, 2013), and regulation of fluid movement in the epididymal lumen, during which water reabsorption increases sperm and protein concentration, creating a hypertonic microenvironment (Turner, 1995; Hermo et al., 2008; Dacheux and Dacheux, 2013).

Immunolocalization studies suggest a complex spatial distribution of many aquaporins in the epididymis (Table 1). AQP0 is found in the epididymis of the stallion but not in the rat, whereas AQP1 is found in the bat and rat myoid cells surrounding the epididymal tubules of the caput region and endothelial cells of the vascular channels throughout the epididymis, but is not found in the mouse. Similarly, AQP3 and -8 are localized in the epididymal basal cells of the rat, which also shows expression of AQP5 in the apical membrane of principal cells of the corpus and cauda regions. In the rat and dog, but not in mouse, AQP7 is expressed in the lateral and/or basal plasma membranes of principal cells in a region-specific manner, and in some basal, clear, and halo cells, as well as in myoid cells enveloping the periphery of epididymal tubules. AQP9 is considered the major aquaglyceroporin of the rat epididymis, and together with AQP2 it is expressed in the principal cells of most epididymal regions and in the cauda clear cells, a pattern of expression that seems to be conserved among mammals. Full expression of AQP9 in principal and clear cells, and of AQP3 in basal cells, requires both testosterone and a lumicrine factor (Badran and Hermo, 2002; Pastor-Soler et al., 2002; Hermo et al., 2004; Oliveira et al., 2005). Products of the kininkallikrein system such as bradykinin might also regulate AQP9 expression in the rat efferent ducts and epididymis through a calcium-dependent mechanism (Belleannee et al., 2009). As shown in Sertoli cells, AQP9 physically interacts with the CFTR and the Na/H exchanger regulatory factor (NHERF1) via a PDZ binding motif in its C-terminus portion in cells of the rat epididymal tubules; this interaction regulates water and glycerol transport through AQP9 (Cheung et al., 2003; Pietrement et al., 2008). Finally, AQP 10 has been noted in endothelial cells of vascular channels of the rat epididymis, whereas AQP 11 is present mainly on the microvilli of principal cells and some basal and halo cells. As in the efferent ducts, the simultaneous expression of aquaporins and aquaglyceroporins in the epididymal epithelium possibly ensures maximum efficiency, redundancy, and selectivity to transport water, glycerol, and glycerylphosphorylcholine to the lumen, thus helping to support and maintain sperm maturation (Hermo and Smith, 2011; Arrighi, 2014).

Teleost testis and efferent ducts

A number of studies in teleosts have reported mRNA expression of different aquaporin paralogs in the testis (Cerda and Finn, 2010; Tingaud-Sequeira et al., 2010; Zapater et al., 2011; Kagawa et al., 2011; Takei et al., 2015). However, immunolocalization studies using paralogspecific antibodies have only been carried out in the gilthead seabream, where RT-PCR and Western blot analyses have confirmed the expression of Aqp0a, -1aa, -1ab, -7, -8b, -9b, and -10b in the testis (Table 1). In the Atlantic halibut (Hippoglossus hippoglossus), the presence of Aqp1ab mRNA and protein has also been reported (Zapater et al., 2011). In contrast, neither aqp3a nor -4a transcripts were detected in the seabream testis or sperm (Chauvigne et al., 2013), similar to findings in the salmonid rainbow trout (Oncorhynchus mykiss), where aqp3a testicular expression was not found (Takei et al., 2015). However, in the zebrafish (Danio rerio), testicular expression of aqp3a and -3b, as well as of aqp1aa, -lab, -4, -7, -8aa, -10b, and -12, has been reported (Tingaud-Sequeira et al., 2010). Therefore, it appears that testicular expression of at least aqp1like, -7, -8-like, and -10b paralogs is a conserved trait between evolutionary distant teleosts.

Immunofluorescence microscopy experiments on the seabream testis showed that among the seven aquaporins investigated, only Aqp0a and -7 are specifically localized in the Sertoli cells, whereas Leydig cells exclusively express Aqp9b (Table 1). The presence of Aqp0a and -9b in Sertoli and Leydig cells of seabream, respectively, is conserved with respect to most mammals, where they may have similar functions, while Aqp7 localization in Sertoli cells seems to be unique for the seabream. In addition, seabream Aqp0a and -8b proteins were not detected in Leydig and Sertoli cells, respectively, in contrast to human and rat. However, it is still possible that other Aqp0 and -8 paralogs, such as Aqp0b and -8aa, the latter being phylogenetically closer to the tetrapod AQP8 than to Aqp8b (Cerda and Finn, 2010), are present in seabream somatic cells. In rats, AQP0 is mainly expressed in Sertoli cells of seminiferous tubules containing elongated spermatids (Hermo et al., 2004), whereas in seabream aqp0a expression in Sertoli cells is up-regulated in vitro by through 11 -KT synthesis at the onset of spermatogenesis (Boj et al., unpubl. data), suggesting the need for this channel during early germ cell development.

Aquaporin localization in seabream germ cells shows a complex pattern of expression, as in mammals. Five aquaporins, Aqp1ab, -7, and -10b, are expressed in all germ cells, from spermatogonia to luminal spermatozoa, whereas Aqp1aa and -8b are only found in haploid cells (Table 1). These observations suggest that the Aqp1ab, -7, and -10b channels may mediate fluid movement during cell volume reductions and the passage of nutritive molecules from Sertoli cells. However, because these paralogs are prevalent in newly formed spermatozoa in the testis, a coordinated synthesis and storage of these channels in intracellular vesicles during germ cell development may also occur. Interestingly, in the seabream the teleost-specific Aqp1ab is the first paralog to be translated in spermatogonia before the onset of spermatogenesis (Boj et al., unpubl. data), which reflects the situation in oocytes where Aqp1ab is synthesized early in oogenesis and plays a crucial role later during hormone-induced meiosis reinitiation and hydration (Fabra et al., 2005; Zapater et al., 2011, 2013). However, Aqp1ab synthesis in early oocytes is activated by triggered progestins (Zapater et al., 2012, 2013), whereas spermatogonial Aqp1ab seems to be up-regulated exclusively by androgens and estrogens produced in vitro (Boj et al., unpubl. data).

In contrast to mammals, initial aquaporin immunolocalization studies in the seabream efferent duct epithelia could only consistently detect the presence of Aqp10b (Table 1). Nevertheless, this paralog is restricted to the apical membrane of flat and elongated epithelial cells (Chauvigne et al., 2013), and thus is similar to the localization of AQP 10 in rat efferent ducts (Hermo et al., 2004). Interestingly, Aqp10b immunoreaction in the seabream epithelial cells was also detected in the membrane of cytoplasmic vesicles, which resembles the AQP9 localization in endosomes of some clear cells of the rat cauda epididymis (Hermo and Smith, 2011). As suggested for mammals, Aqp10b in the teleost efferent ducts may be involved in water resorption mechanisms and in providing glycerol as an aerobic metabolic substrate during maturation of spermatozoa (Cooper and Brooks, 1981). In rat, AQP3 and -11 are also found in the efferent duct and epididymal epithelium. Therefore, it is possible that the teleost orthologs, which have not yet been investigated, are also present in the luminal epithelium of the efferent ducts.

Role of Aquaporins during Sperm Motility

The mammalian and teleostean spermatozoa

Mammalian spermatozoa consist of a head, neck, and tail (Fig. 1). The head contains the nucleus, which is surrounded by the cytoskeletal structures and a thin cytoplasm. The nucleus is characterized by a highly condensed chromatin and its shape is species-specific, although usually flattened dorsoventrally (Pesch and Bergmann, 2006). The anterior tip of the nucleus is covered by the acrosome, which contains hydrolytic enzymes necessary for the penetration of sperm into the oocyte during fertilization (Eddy, 2006). In the continuity of the head, the flagellum developed from a centriole is the motile apparatus implicated in sperm movement (Inaba, 2003; Jan et al., 2012). The spermatozoon flagellum is divided into four distinct segments: the connecting, middle, principal, and end pieces, and it is composed of four major structural components: the axoneme that spans the whole length of the flagellum, the outer dense fibers surrounding the axoneme in the middle and principal pieces, the mitochondrial sheath located in the middle piece surrounding the outer dense fibers and axoneme, and the fibrous sheath in the principal piece (Inaba, 2011). Usually, the axoneme is formed by nine outer doublet microtubules and two central singlet microtubules (the 9+2 pattern); the active sliding of microtubules by axonemal dyneins and proper assembly of all cytoskeletal elements is critical for sperm motility (Inaba, 2003). Moreover, the mitochondrial sheath plays an important role in generating the necessary energy to sustain flagellar motility (Sun and Yang, 2010). Finally, the spermatozoon plasma membrane contains glycoproteins and lipids, which form domains with regional compositions that confer specific functions (Pesch and Bergmann, 2006).

While most mammalian spermatozoa have the general characteristics described above, teleost spermatozoa are more divergent in form and structure. They can be aflagellate or biflagellate, and vary in shape, size, structure, and number and location of organelles (Jamieson et al., 1991). In general, the teleost spermatozoon is anacrosomal, has a head with a small ovoid or spherical nucleus, and a short midpiece containing one or few mitochondria (Fig. 1) (Lahnsteiner and Patzner, 2008). However, depending on ultrastructural features, teleost sperm can be classified into two groups: the introsperm group, which shows spermatozoa with an elongated nucleus and a large midpiece with numerous mitochondria typical of internal fertilizers, and the aquasperm group, characteristic of external fertilizers in which spermatozoa exhibit a flagellar axis perpendicular or parallel to the nucleus, depending on whether nuclear rotation occurs during spermiogenesis (Jamieson et al., 1991). As in mammals, the axoneme flagellum is the motile apparatus of the common 9+2 microtubular pattern, and under hydrolysis of ATP the sliding process of microtubules by dyneins allows flagellar beating (Cosson et al., 2008a, b). In some teleostean groups, such as in anguilliforms and elopiforms, the sperm flagellum presents a 9+0 pattern without the central microtubules (Lahnsteiner and Patzner, 2008). The spermatozoon plasma membrane also plays an important role during activation of sperm motility in teleosts, since it is the primary detector of changes in the environmental osmolarity and ion concentration, and is the key component in the sperm-egg fusion mechanism (Cosson, 2004).

Activation of sperm motility in mammals and teleosts

In the mammalian cauda epididymis, sperm acquires the ability to move progressively, but the functional maturation of spermatozoa is not completed at this stage as they are still unable to fertilize the egg (Eddy, 2006). Following ejaculation into the female reproductive tract, the spermatozoa go through several physiological changes that make them competent for fertilization. During this process, known as capacitation, spermatozoa experience a cholesterol efflux from the plasma membrane, which hyperpolarizes and increases its fluidity, resulting in the modulation of the ion concentration in the sperm and an increased protein phosphorylation (Visconti et al., 2002). Spermatozoa also acquire vigorous swimming activity in the vicinity of the ova, the so-called hyperactivation phase, which is needed to traverse the zona pellucida after the acrosome reaction to fertilize the egg (Baldi et al., 1996; Suarez, 2008). Hyperactivation is triggered by an increase in flagellar [Ca.sup.2+], which enters through plasma membrane cation channels of the sperm, also known as CatSper channels, as well as by the release of [Ca.sup.2+] from intracellular stores (Suarez, 2008). Sperm hyperactivation also requires an increase in pH and ATP production, the latter being synthesized from glycolysis and/or mitochondrial oxidative phosphorylation (OXPHOS), depending on the species (Piomboni et al., 2012).

In teleosts, spermatozoa remain quiescent in the testes and efferent ducts and activation of motility is induced by the hypo- or hyperosmotic aquatic environment into which the sperm are ejaculated (Billard, 1986; Cosson, 2004). In FW teleosts, the release of spermatozoa into the hyposmotic external medium induces membrane hyperpolarization, which leads to a [K.sup.+] efflux and a transient increase in intracellular [Ca.sup.2+] and cAMP (Morisawa and Suzuki, 1980; Morisawa et al., 1983; Cosson et al., 1989; Tanimoto et al., 1994). The subsequent cAMP-dependent phosphorylation of axonemal proteins and dynein light chain triggers the movement of the flagellum (Hayashi et al., 1987; Inaba et al., 1999). This mechanism, however, is not general for all FW teleosts since, in some species, [Na.sup.+]/[Ca.sup.2+] and [Na.sup.+]/[H.sup.2+] exchangers and voltage-sensitive [Ca.sup.2+] channels participate in motility initiation (Marian et al., 1997; Krasznai et al., 2003). Very few species of marine teleosts have been studied to date. The current models suggest that sperm motility is activated by osmotic shock, caused by the increase in osmolality of seawater (SW) (from ~350 mOsm to 1000 mOsm). The osmotic shock, in turn, causes an increase in intracellular [Ca.sup.2+] concentration as a consequence of stretch-activated channels (SACs) or [Ca.sup.2+] channel activation, the release of [Ca.sup.2+] from intracellular stores, or as a result of increased cytosol concentration following massive water efflux (Cosson et al., 2008a, b; Zilli et al., 2012). In Pacific herring (Clupea pallasi), however, sperm motility is initiated by sperm-activating peptides derived from the egg (Cherr et al., 2008), which activate [Na.sup.+]/[Ca.sup.2+] exchange, causing [Na.sup.+] efflux and an influx of [Ca.sup.2+] (Vines et al., 2002). In marine spermatozoa, activation of the axonemal machinery is achieved directly by the increase of [Ca.sup.2+] and other ions, or by [Ca.sup.2+]/calmodulin- or cAMP-dependent protein phosphorylation/dephosphorylation of structural components of axonemal dyneins, kinases, and phosphatases anchored in the axoneme and in the radial spoke proteins (Zilli et al., 2012).

Aquaporins in mammalian sperm

When sperm is ejaculated into the female reproductive tract, microenvironmental osmolality is lower than in the male tract; this relatively hypo-osmotic shock induces sperm cell swelling, which provokes a regulatory volume decrease response by the efflux of osmolytes and water to counteract the osmotic stress (Callies et al., 2008; Chen et al., 2011; Chen and Duan, 2011). This mechanism is critical for fertilization by the sperm, since inhibition of volume regulation in ejaculated spermatozoa induces a decrease in sperm velocity and hence failure to penetrate and migrate through the cervical mucus of the oviduct (Yeung and Cooper, 2001; Cooper et al., 2004). It has been hypothesized that the osmolytes needed for regulatory volume decrease are acquired by spermatozoa from the epididymal epithelium through the membrane-bound droplet of cytoplasm on the midpiece, which is facilitated by the hypertonicity of the epididymal luminal fluid (Cooper and Yeung, 2003).

It is well known that mammalian sperm has a higher water permeability than other cell types (Nodes et al., 1993; Curry et al., 1995a), and ion channel-controlled water influx/efflux is involved in postcopulatory sperm volume regulation (Petrunkina et al., 2004; Yeung et al., 2005; Callies et al., 2008). Since water permeability of the spermatozoa of some mammals is sensitive to mercury and phloretin (Curry et al., 1995b; Yeung et al., 2009a), which are known inhibitors of aquaporin conductance (Haddoub et al., 2009), a potential role of aquaporins in volume regulation has been suggested. Several studies have supported this hypothesis, confirming that the epididymal spermatozoa of most mammals express AQP3, -7, -8, and possibly AQP11, whereas AQP2 and -4 expression has been reported in cat and rat, respectively (Table 1).

In mouse and human, but not in rat, AQP3 is found in the principal piece of the sperm tail membrane (Fig. 1), a region where volume regulatory processes occur. The role of AQP3 in these processes was recently demonstrated using AQP3-null mice (Chen et al., 2011). In this model, the sperm shows normal motility activation in response to hypotonicity upon ejaculation, but it displays impaired sperm volume regulation and progressive cell swelling at the level of the cytoplasmic droplet, which increases tail bending and hampers sperm migration in the oviduct, resulting in reduced fertilization (Chen et al., 2011). However, the molecular mechanism by which AQP3 prevents swelling in normal sperm is unclear, because in AQP3-mutant sperm, in which water influx and efflux are supposed to be equally diminished during regulatory volume decrease if AQP3 is considered an inert pore, the progressive sperm cell swelling should not have been observed (Chen and Duan, 2011). As suggested for other biological systems (Hill and Shachar-Hill, 2015), AQP3 may function as an osmosensor/mechanosensor in spermatozoa to detect early events in cell swelling and to convey signals to stimulate the regulatory volume decrease response through interaction with volume-sensitive ion channels or cytoskeletal components (Chen et al., 2011; Chen and Duan, 2011). This hypothesis has not yet been demonstrated, but it is supported by the finding that AQP4 or -5 can interact with the volume-sensitive calcium channel TRPV4 in mouse astrocytes and salivary glands for the regulation of cell volume under hypotonic stimulation (Liu et al., 2006; Benfenati et al., 2011), as well as by the direct interaction of AQP2 with the cytoskeletal protein actin (Noda and Sasaki, 2006).

Mammalian spermatozoa also express AQP7, -8, and AQP11 (Fig. 1), although in human only AQP11 mRNA has been demonstrated in the testis (Yeung and Cooper, 2010). In rat and boar, AQP7 is detected at the level of the midpiece, including the cytoplasmic droplet, and the most anterior region of the tail, whereas in human ejaculated sperm AQP7 localizes in the pericentriolar region of the neck, midpiece, and different regions along the tail. In the boar, AQP7 is more localized in the connecting piece of spermatozoa, the most anterior region of the midpiece below the head, which may be important for oscillation of sperm flagella (Ounjai et al., 2012). Interestingly, in human swim-up motile sperm, part of AQP7 seems to relocalize to the mitochondria of the midpiece (Moretti et al., 2012). In contrast, AQP8 is present exclusively in the midpiece of rat spermatozoa or along the tail as granular patches in human and mouse sperm, and AQP11 appears at the distal tail of rat and murine spermatozoa. In boar spermatozoa, however, AQP11 has been described in the head and midpiece, and diffuse labeling is also seen along the tail.

The physiological roles of AQP7, -8, and -11 in sperm remain unknown. In human ejaculated sperm, low AQP7 levels seem to correlate with impaired progressive motility (Yeung et al., 2009b), and it has been suggested that AQP7 might have a role in the transport of glycerol as an energy substrate during sperm maturation and storage (Yeung, 2010). Studies using quinine and mercury on wild-type and AQP7-null mice sperm suggest that AQP8, but not AQP7, is involved in volume regulation (Yeung et al., 2009a), and therefore AQP8 might function together with AQP3 to regulate this process. This view is reinforced by the observation that sperm volume increase and partial recovery occurred faster in the AQP7 knockout mice that showed a higher expression of testicular AQP8 mRNA, which can be interpreted as an indication of more AQP8 water channels in the knockout spermatozoa (Yeung et al., 2009a).

Aquaporin localization and function in teleost spermatozoa

The potential role of aquaporins during activation of sperm motility in teleosts was first suggested by Cosson and collaborators, based on the fact that sperm motility of marine teleosts such as turbot (Scophthalmus maximus) and European seabass (Dicentrarchus labrax) is sensitive to low levels of mercury (Cosson et al., 1999; Alavi and Cosson, 2006; Abascal et al., 2007). The mercurial inhibition of sperm motility has also been reported for FW fishes, such the catfish Clarias gariepinus (Rurangwa et al., 1998), the European perch Perca fluviatilis (Hatef et al., 2011), or salmonids such as the rainbow trout (Dietrich et al., 2010; Takei et al., 2015) and the chum salmon Oncorhynchus keta (Takei et al., 2015). In some of these species, the concentrations of mercury that were effective on intact sperm had no effect on the axonemal apparatus of demembranated spermatozoa (Cosson et al., 1999) or on glycerol-activated sperm (Takei et al., 2015), suggesting that the motile apparatus is not directly compromised by low concentrations of Hg[Cl.sub.2]. Therefore, it is possible that sperm water fluxes triggered by hypo- and hyperosmotic shock may be mediated by aquaporins of the spermatozoon plasma membrane (Alavi and Cosson, 2006).

Immunolocalization studies in the seabream have confirmed that, as in the testis, multiple aquaporins are present in the spermatozoon (Table 1). In the seabream model, ejaculated spermatozoa show a segregated spatial distribution of Aqp 1 aa and -7 in the entire flagellum or the head, respectively, whereas Aqp1ab, -8b, and -10b are both in the head and the anterior tail. Upon SW activation, Aqp10b and -1ab are rapidly phosphorylated and translocated to the head plasma membrane, while Aqp8b accumulates in the single spermatozoon mitochondrion and Aqp1aa and -7 remain unchanged (Fig. 1) (Chauvigne et al., 2013). Exposure of seabream sperm to mercury inhibits motility, which can be reversed by the reducing agent [beta]-mercaptoethanol, to which mercury-inhibited Aqp1aa, but not Aqp10b, is sensitive (Santos et al., 2004; Zilli et al., 2009). Similarly, the addition of another reducing compound such as dithiothreitol (DTT) to Hg[Cl.sub.2]-treated sperm abolishes mercurial inhibition of sperm motility in salmonids (Takei et al., 2015). Based on these observations, it has been proposed that in marine teleosts Aqp1aa possibly mediates the water efflux during hyperosmotic shock, followed by cytosolic concentration of intracellular [Ca.sup.2+] and activation of cAMP-mediated phosphorylation of proteins required for sperm motility (Zilli et al., 2009, 2011). In salmonids, however, Aqp1aa may mediate the cell volume regulatory mechanism activated upon ejaculation in the hypotonic environment, thus contributing to maintenance of the integrity of the sperm plasma membrane, as seems to occur in mammalian sperm (Takei et al., 2015). In the seabream, the role of Aqp1aa in water efflux would be consistent with the distribution of this channel along the entire flagellum of non-motile spermatozoa (Chauvigne et al., 2013), which, on SW exposure, would allow an osmotic response within milliseconds (Cosson et al., 2008b). However, mercurial compounds can affect the function of ion channels (Sirois and Atchison, 1996; Hisatome et al., 2000), which may also be present in the plasma membrane of the fish sperm and play a role in the reception of the activation signal (Dzyuba and Cosson, 2014). In addition, mercurial inhibition of seabream Aqp1ab and -7, which are also present in sperm, can be reversed by [beta]-mercaptoethanol, as in Aqp1aa (Chauvigne et al., 2013). Therefore, the physiological role of Aqp1aa during activation or maintenance of sperm motility in teleosts, as well as the roles of Aqp1ab, -7, and -10b, remain intriguing.

Recent studies on seabream, however, have uncovered a function of Aqp8b in sperm beyond water transport. This aquaporin, which is phosphorylated on SW activation, as are Aqp1ab and -10b, is the only paralog that is rapidly (i.e., in less than one second after activation) inserted into the inner membrane of the spermatozoon mitochondrion (Chauvigne et al., 2013, 2015). Since many aquaporin paralogs, such as AQP8, can transport hydrogen peroxide ([H.sub.2][O.sub.2]) in addition to water (Bienert and Chaumont, 2014; Almasalmeh et al., 2014), and mitochondrial OXPHOS seems to be a major source of ATP in fish spermatozoa during the motility phase (Dreanno et al., 1999, 2000; Lahnsteiner and Caberlotto, 2012), Chauvigne et al. (2015) hypothesized that [H.sub.2][O.sub.2] produced as a byproduct during OXPHOS (Collins et al., 2012), as well as accumulated in the mitochondria due to the hyperosmotic stress (McCarthy et al., 2010), might be transported out of this compartment by Aqp8b. To test this hypothesis, these authors employed an affinitypurified antibody specific for seabream Aqp8b, which blocked the intracellular transport of Aqp8b in the spermatozoa, possibly through steric inhibition of the trafficking mechanism as well as channel permeability once inserted in the mitochondria. With this antibody and a mitochondriatargeted antioxidant, it was shown that Aqp8b operates as a mitochondrial peroxiporin in activated sperm of seabream to allow the efflux of accumulated [H.sub.2][O.sub.2], thus maintaining the mitochondrial membrane potential and the production of ATP needed for the maintenance of flagellar motility (Chauvigne et al., 2015). These findings indicate that mitochondrial Aqp8b in seabream spermatozoa plays an essential role in avoiding oxidative damage by reactive oxygen species (ROS) such as [H.sub.2][O.sub.2], and thus preserves flagellar motility under hypertonic conditions. Interestingly, rapid transport of an AQP8 ortholog into the mitochondria of activated spermatozoa was also noted recently in the Atlantic salmon Salmo salar (Chauvigne et al., unpubl. data). These observations suggest that the Aqp8-mediated detoxification mechanism may have evolved in the sperm of teleosts as a selective advantage for increased sperm competition (Chauvigne et al., 2015).

The role of mitochondrial, AQP8-like channels to alleviate oxidative stress in activated spermatozoa might be teleost-specific. In mammals, AQP8 has not been localized specifically in the mitochondria of spermatozoa (Calamita et al., 2005; Yeung, 2010; Yeung et al., 2010), unlike in hepatic (Calamita et al., 2005) and renal proximal tubule (Molinas et al., 2012) cells, where AQP8 is present in the inner mitochondrial membrane and is thought to mediate ammonia and [H.sub.2][O.sub.2] transport (Soria et al., 2010; Marchissio et al., 2012). However, in human motile sperm, AQP7 is detected in the mitochondria (Moretti et al., 2012) and thus it can potentially transport peroxide, as has been shown for other mammalian aquaglyceroporins in somatic cells such as AQP3 (Miller et al., 2010; Hara-Chikuma et al., 2012). Therefore, aquaporins might function as peroxiporins in mammalian spermatozoa, particularly during the hyperactivation process, which is reminiscent of the high motility of marine fish sperm (Oda and Morisawa, 1993; Cosson et al., 2008b) and which requires increased levels of ATP (Suarez, 2008). In some mammals, however, mitochondria-derived ATP is not crucial for sperm motility but cytoplasmic glycolysis may be the main ATP supplier (Piomboni et al., 2012). In these species, the relevance of aquaporin-mediated [H.sub.2][O.sub.2] transport in mitochondria might be associated with the production of ROS, which in controlled levels is needed for proper sperm function (Amaral et al., 2013). In any event, the role of aquaporins as functional peroxiporins in mammalian spermatozoa merits further investigation.

Conclusions

Current information on the biology of aquaporins in the mammalian and teleost male reproductive tract and spermatozoa suggests that several of these channels might have conserved roles in vertebrates controlling germ cell development, sperm maturation, nutrition, and volume changes occurring during sperm activation. In teleosts, however, comprehensive studies have been conducted only in the gilthead seabream. Therefore, more data are needed on FW fish, and particularly in euryhaline species that reproduce in environments of varying salinities (Morita et al., 2003). Since teleosts harbor a larger repertoire of aquaporin orthologs than mammals (Finn et al., 2014), it would also be critical to investigate whether specific teleost aquaporin paralogs have neofunctionalized to acquire novel or specialized physiological functions in sperm, which may be the case for the mitochondrial Aqp8 orthologs.

The specific physiological functions of the multiple aquaporin paralogs expressed in the testis and spermatozoa nevertheless remain poorly understood. The available genetic models do not show clear phenotypes, or are not suitable to reveal gonad defects; and no aquaporin-specific inhibitors are currently available. Therefore, it would be desirable to explore alternative approaches to investigate aquaporin function, such as the use of paralog-specific antibodies, which has been successful in uncovering the role of Aqp8b in seabream sperm. Although spermatozoa have a limited amount of RNA and are considered to be transcriptionally silent, some mRNAs can be translated in sperm by mitochondrial ribosomes (Gur and Breitbart, 2006). This finding suggests that RNAi knockdown approaches might be useful to elucidate the function of ion channels and aquaporins during sperm activation. In fact, this method has been used to silence CatSper2 in rat spermatozoa via electroporation of siRNA duplexes, showing that targeted disruption of CatSper2 prevents [Ca.sup.2+] influx and decreases the rate of hyperactivated sperm (Zhang et al., 2011). The studies in seabream spermatozoa suggest the existence of intracellular pathways for aquaporin trafficking, which allow the rapid translocation of Aqp1ab and -10b into the sperm plasma membrane and of Aqp8b to the mitochondrion upon activation. Although these putative aquaporin trafficking mechanisms in seabream sperm have not been identified, and have not yet been described for mammalian spermatozoa, they can offer additional avenues to clarify the physiological functions of aquaporins and their regulation. They, too, need to be considered.

Despite these limitations, investigation into the role of aquaporins in the male reproductive system of vertebrates has highlighted the function of aquaporins beyond water transport, such as the role of Aqp8b as a peroxiporin in seabream spermatozoa, or the possible role of AQP3 as an osmosensor/mechanosensor to regulate the volume decrease response in ejaculated mammalian sperm. The study of these processes with original approaches might uncover novel mechanisms of aquaporin physiology, contributing greatly to our understanding of the molecular basis of male fertility.

Acknowledgments

The work was funded by the Spanish Ministry of Economy and Competitivity (MINECO) projects AGL2010-15597 and AGL2013-41196-R, and Generalitat de Catalunya projects 2009 SGR 01050 and 2014 SGR 1351, to J.C. M.B. was a recipient of a predoctoral fellowship from MINECO (BES-2011-049399).

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MONICA BOJ (1), FRANCOIS CHAUVIGNE (1,2), AND JOAN CERDA (1,*)

(1) Institut de Recerca i Tecnologia Agroalimentaries (IRTA)-Institut de Ciencies del Mar, Consejo Superior de Investigaciones Cientificas (CSIC), 08003 Barcelona, Spain; and (2) Department of Biology, Bergen High Technology Centre, University of Bergen, 5020 Bergen, Norway

Received 17 February 2015; accepted 24 April 2015.

(*) To whom correspondence should be addressed. E-mail: joan.cerda@irta.cat

Abbreviations: 11-KT, 11-ketotestosterone; AQP, aquaporin; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CFTR, cystic fibrosis transmembrane conductance regulator; FSH, follicle-stimulating hormone; LH, luteinizing hormone; NHERF, Na/H exchanger regulatory factor; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; RT-PCR, reverse transcription polymerase chain reaction.

Table 1
Distribution of aquaporins in the male reproductive tract of mammals
and the teleost gilthead seabream

Paralog                                            Testis (1)
Mammals/Seabream    Species          Int   Lc  Sc  Spg  Spc  Spd  Sp (2)

AQPO/Aqp0a          Rat               -    +   +    -    -    -    -
                    Stallion          -    +   -    -    -    +    -
                    Seabream          -    -   +    +    -    -    -
AQP 1/Aqp1aa, -1ab  Mouse             +    -   -    -    -    -    -
                    Rat               -    -   -    -    -    -    -
                    Hamster           nr   nr  nr   nr   nr   nr   nr
                    Bat               -    -   -    -    -    +    -
                    Cat               +    -   -    -    -    -    -
                    Dog               nr   nr  nr   nr   nr   nr   nr
                    Seabream Aqp1aa   -    -   -    -    -    +    +
                    Seabream Aqp1ab   -    -   -    +    +    +    +
AQP2                Rat               nr   nr  nr   nr   nr   nr   nr
                    Cat               -    +   -    -    -    -    -
                    Dog               nr   nr  nr   nr   nr   nr   nr
                    Stallion          -    +   -    -    -    +    -
AQP3                Human             nr   nr  nr   nr   nr   nr   nr
                    Mouse             -    -   -    -    -    -    +
                    Rat               -    -   -    -    -    -    -
AQP4                Rat               nr   nr  +    nr   nr   nr   nr
AQP5                Rat               nr   nr  nr   nr   nr   nr   nr
                    Cat               -    -   -    -    -    -    -
                    Stallion          -    +   -    -    -    +    -
AQP7/Aqp7           Human             -    -   -    -    -    +    +
                    Mouse             -    -   -    -    -    +    +
                    Rat               -    -   -    -    +    +    +
                    Dog               nr   nr  nr   nr   nr   nr   nr
                    Boar              nr   nr  nr   nr   nr   nr   nr
                    Seabream          -    -   +    -    +    +    +
AQP8/Aqp8b          Human             -    -   +    +    +    +    +
                    Mouse             -    -   -    +    +    +    +
                    Rat               -    -   +    +    +    +    +
                    Seabream          -    -   -    -    -    +    +
AQP9/Aqp9b          Human             -    +   +    +    +    +    nr
                    Mouse             nr   nr  nr   nr   nr   nr   nr
                    Rat               -    +   +    -    +    -    -
                    Hamster           nr   nr  nr   nr   nr   nr   nr
                    Bat               -    -   -    -    -    -    -
                    Cat               -    +   -    -    -    -    -
                    Dog               -    -   -    -    -    -    -
                    Stallion          -    +   -    -    -    +    -
                    Seabream          -    +   -    -    -    -    -
AQP10/Aqp10b        Rat               -    -   -    -    -    -    -
                    Seabream          -    -   +    +    +    +    +
AQP11               Mouse             -    -   -    -    -    +    +
                    Rat               -    -   -    -    +    +    +
                    Boar              nr   nr  nr   nr   nr   nr   nr

Paralog              Efferent duct (1)    Epididymis (1)
Mammals/Seabream        E     Spz           E    Spz

AQPO/Aqp0a              -      -            -     -
                        nr     nr           +     nr
                        -      -
AQP 1/Aqp1aa, -1ab      +      -            -     nr
                        +      -            +     -
                        +      nr           -     nr
                        +      -            +     -
                        +      -            -     -
                        +      -            -     -
                        -      +
                        -      +
AQP2                    nr     nr           +     -
                        -      -            +     +
                        +      -            +     -
                        nr     nr           +     nr
AQP3                    nr     nr           nr    +
                        nr     nr           -     +
                        -      -            +     -
AQP4                    nr     nr           -     +
AQP5                    -      -            +     -
                        -      -            -     -
                        nr     nr           +     nr
AQP7/Aqp7               nr     nr           nr    +
                        nr     nr           -     +
                        +      nr           +     +
                        -      -            +     -
                        nr     nr           nr    +
                        -      -
AQP8/Aqp8b              nr     nr           nr    +
                        nr     nr           -     +
                        -      nr           +     +
                        -      +
AQP9/Aqp9b              nr     +            -
                        +      -            +     -
                        +      nr           +     -
                        +      nr           +     nr
                        -      -            +     -
                        +      -            +     -
                        +      -            +     -
                        nr     nr           +     nr
                        -      -
AQP10/Aqp10b            +      -            +     -
                        +      -
AQP11                   nr     nr           nr    +
                        nr     +            +
                        nr     nr           nr    +

Paralog
Mammals/Seabream         Reference (3)

AQPO/Aqp0a                 (1)(2)
                           (3)
                           (4)(5)
AQP 1/Aqp1aa, -1ab         (6)(7)
                           (2)(6)(8)(9)(10)
                          (11)
                          (12)
                          (13)
                          (14)
                           (4)(15)
                           (4)
AQP2                      (16)
                          (13)
                          (14)
                           (3)
AQP3                      (17)
                          (17)
                           (1)
AQP4                      (16)(18)
AQP5                       (2)(16)(19)
                          (13)
                           (3)
AQP7/Aqp7                 (20)
                          (21)
                          (19)(22)(23)(24)(25)(26)
                          (14)
                          (27)
                           (4)(5)
AQP8/Aqp8b                (20)
                          (28)(29)
                           (9)(24)(25)(26)(28)(30)
                           (4)
AQP9/Aqp9b                (20)(31)(32)
                           (2)(6)
                           (2)(9)(10)(19)(30)(31)(33)(34)(35)
                          (11)
                          (12)
                          (13)
                          (14)
                           (3)
                           (4)
AQP10/Aqp10b               (1)
                           (4)(5)(15)
AQP11                     (36)
                          (19)(36)
                          (27)

The table is based on immunocytochemistry and immunofluorescence
microscopy data obtained using specific antibodies (-, not detected; +,
detected; nr, not reported).
(1) Abbreviations: Int, uncharacterized interstitial cells; Lc, Leydig
cell; Sc, Sertoli cell; Spg, spermatogonia; Spc, spermatocyte; Spd,
spermatid; Spz, spermatozoa; E, epithelium.
(2) For seabream, testicular spermatozoa in the lumen of the
seminiferous lobules show the same pattern of aquaporin expression as
that of ejaculated sperm.
(3) References: (1) Hermo et al., 2004; (2) Da Silva et al., 2006a; (3)
Klein et al., 2013; (4) Chauvigne et al., 2013; (5) Boj et al.
(unpubl.); (6) Ruz et al., 2006; (7) Lu et al., 2008; (8) Fisher et
al., 1998; (9) Badram and Hermo 2002; (10) Oliveira et al., 2005; (11)
Ford et al., 2014; (12) Oliveira et al., 2013; (13) Arrighi and Aralla,
2014; (14) Domeniconi et al., 2008; (15) Zilli et al., 2009; (16) Da
Silva et al., 2006b; (17) Chen et al., 2011; (18) Jesus et al., 2014b;
(19) Hermo et al., 2008; (20) Yeung et al., 2010; (21) Skowronski et
al., 2007; (22) Ishibashi et al., 1997; (23) Suzuki-Toyota et al.,
1999; (24) Kageyama et al., 2001; (25) Calamita et al., 2001a; (26)
Calamita et al., 2001b; (27) Prieto-Martinez et al., 2014; (28) Yeung
et al., 2009a; (29) Yang et al., 2005; (30) Elkjaer et al., 2001; (31)
Pastor-Soler et al., 2001; (32) Arena et al., 2011; (33) Nihei et al.,
2001; (34) Belleannee et al., 2009; (35) Jesus et al., 2014a; (36)
Yeung and Cooper, 2010.
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Publication:The Biological Bulletin
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Date:Aug 1, 2015
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