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REVIEW |
Department of Physiology and Biophysics, Robert Wood Johnson Medical School-UMDNJ, 675 Hoes Lane West, Piscataway, New Jersey 08854, USA 1 Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, 84 Lipman Drive, New Brunswick, New Jersey 08901-8525, USA
(Correspondence should be addressed to R Zachow; Email: zachowrj{at}umdnj.edu)
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Abstract |
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 Top Abstract The hepatocyte growth factor...Ovarian functionConcluding thoughtsReferences |
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The hepatocyte growth factor (HGF) system |
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TopAbstractThe hepatocyte growth factor...Ovarian functionConcluding thoughtsReferences |
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HGF is synthesized as an inactive 97 kDa single chain precursor, and is processed to yield its bioactive disulfide-linked heterodimer (Miyazawa et al. 1989, Nakamura et al. 1989). Another component of the HGF system is HGF activator (HGFA) protein. This molecule is a serine protease which cleaves the immature HGF precursor molecule to form mature bioactive HGF (Miyazawa et al. 1993). Thus, the concomitant presence of both HGF and HGFA within a tissue microenvironment is presumed to exert some level of control upon HGF bioactivity. Relatively little is known about the regulation of HGFA expression; however, the presence of HGFA has been established within the rat ovary (discussed below; Uzumcu et al. 2006).
The most recent addition of the HGF system to be identified is HGFA inhibitor protein (HAI; Shimomura et al. 1997). This protein is a Kunitz-type serine protease inhibitor, which, as the name implies, blocks the activation of HGFA. One study to date has demonstrated the presence of the mRNAs encoding HAI-1 and HAI-2 within the human testis (Yamauchi et al. 2002). The function of HAI has not been reported within the testis, and neither the expression nor functions of HAI have been described within the ovary.
The HGF receptor, identified as the p190 c-met proto-oncogene, is a member of the receptor tyrosine kinase family (Bottaro et al. 1991). In its mature bioactive form, plasma membrane-bound c-met comprises disulfide-linked 
and ß chains; with a protein tyrosine kinase (PTK) domain (residues Y1349 and Y1356) nested within carboxyl terminus of the ß chain (Gonzatti-Haces et al. 1988, Giordano et al. 1989, Peruzzi & Bottaro 2006). Upon activation by HGF, c-met PTK activity is coupled to the recruitment of several adaptor proteins including the non-receptor PTK Src, the adaptor protein SHC, growth factor receptor-bound protein 2 (Grb2), and Grb-2-associated binder (Gab1) (Peruzzi & Bottaro 2006), followed by mobilization of numerous signaling cascades. Examples of HGF-induced signaling motifs include those mediated by cyclic nucleotides, phosphosinositide-3 kinase (PI-3K)/protein kinase B (Akt), mitogen-activated protein kinases, calcium-phospholipids/protein kinase C, and Janus kinase/signal transducer and activator of transcription (Baffy et al. 1992, Lail-Trecker et al. 1998, Liu 1999, Zachow & Woolery 2002, Makondo et al. 2004). Pathways coupled to the regulation of cell cycle progression, morphogenesis, and cell survival are among those under the control of HGF/c-met-dependent signaling (Peruzzi & Bottaro 2006).
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Ovarian function |
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TopAbstractThe hepatocyte growth factor...Ovarian functionConcluding thoughtsReferences |
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Folliculogenesis is a dynamic process during which follicular granulosa cells (GCs) and theca cells proliferate and differentiate to produce factors (e.g., steroid and peptide hormones and growth factors) which, through autocrine, paracrine, and endocrine pathways, support oocyte maturation and enable ovulation. In a general sense, folliculogenesis is dependent upon the pituitary gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Within preovulatory follicles, LH stimulates the production and secretion of the aromatizable androgens (androstenedione and testosterone) in theca cells. Whereas FSH targets GC, and upregulates the expression and activity of cytochrome P450 aromatase (CYP19) enabling the aromatization of theca cell androgens into estradiol-17ß (E2). Ovarian androgens and E2 are necessary for normal reproductive function; importantly, aberrant levels of ovarian steroids have been coupled to infertility and certain reproductive pathologies such as polycystic ovary syndrome (Erickson 1994, Ehrmann 2005). Hence, tight regulation of the production of androgens and E2 is important for controlling both normal and pathologic intra- and extraovarian processes.
Decades of research have shown that several intraovarian growth factors work with the gonadotropins and facilitate folliculogenesis through an array of autocrine and paracrine mechanisms which control follicle growth and steroidogenesis (Webb et al. 2004, Barnett et al. 2006, Knight & Glister 2006). It is important to realize that a number of growth factors have been localized within growing follicles, and many of these work through the activation of receptor PTK, with HGF being one such factor. Some other examples of these which have been shown to regulate important aspects of follicle cell function are insulin and insulin-like growth factor-I (IGF-I), epidermal growth factor, transforming growth factor- (TGF-), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF), neurotrophins, and kit ligand (reviewed in Fortune 2003, Skinner 2005). Interestingly, these receptor PTKs often induce signaling mechanisms common to one another and result in overlapping cell responses. Of course, there are many other growth factors and cytokines (e.g., TGF-ß and its family members, tumor necrosis factor-, interleukins, and others) using non-PTK mechanisms of action; each of which also mobilize some similar signaling cascades (Magoffin 1991, Terranova 1991). Such observations support the belief that an intricate web of cooperation occurs between the gonadotropins and the numerous growth factor/cytokine-dependent control mechanisms which mediate follicle cell differentiation and function. In this review, we suggest that the mesenchymal-epithelial paracrine mechanism, an example of which is mediated by HGF, is one example of the many important components which guide follicle development and ovulation.
Interestingly, of the vast number of follicles that are recruited from the non-growing ovarian follicular reserve to develop during each reproductive cycle (e.g., the menstrual cycle in primates and the estrus cycle in rodents), few (arguably <1%) of these follicles will ever fully mature and ovulate. Instead, all but the so-called selected follicles (i.e., those follicles which will ovulate) die by the process known as atresia. Apoptosis, especially within GC, has been shown to be a predominant cellular mechanism that leads to follicular atresia (Hussein 2005). Based upon a plethora of in vivo and in vitro studies using animal models, FSH is required to maintain follicle (e.g., GC) viability.
It is important to consider that, although FSH is a key folliculogenic hormone, the modulation of FSH bioactivity by intraovarian growth factors also regulates steroidogenesis, and can prevent or promote apoptosis in GC (Hsueh et al. 1996, Kaipia & Hsueh 1997). It seems that gonadotropin action in the ovary is primarily mediated by local growth factors (Hillier 2001, Conti et al. 2006). Using transgenic mice to create selective gene knockouts, it has also been shown that certain intraovarian growth factors are in fact vital for the process of folliculogenesis (Burns & Matzuk 2002, Roy & Matzuk 2006).
The HGF system and folliculogenesis
During the female reproductive lifespan, follicles are recruited from a latent resting pool of primordial follicles into a growing cohort (often referred to as the primordial to primary follicle transition). Throughout the growth phase, follicles pass through several stages of growth and differentiation which involves the exquisite temporal regulation of cell proliferation, morphogenic and functional differentiation, angiogenesis, apoptosis, and motogenesis. Ovulation of the selected follicle results in its rupture with concomitant damage to the ovarian surface epithelium; this is followed by epithelial repair and terminal differentiation of the remnant ovulated follicle into the corpus luteum. As such, the complete course of folliculogenesis (including ovulation and luteogenesis) represents a unique example of ongoing tissue growth with angiogenesis, insult, repair, and degeneration in adult mammals. When considering this, a remarkable comparison can be made between this vital and healthy event and oncogenesis, the latter involving one or more of the aforementioned processes escaping from normal control. Many studies have documented that mutations in HGF, c-met, or overexpression of HGF and/or c-met occur in numerous cancers (e.g., breast, prostate, ovarian surface epithelial, non-small cell lung, and others; Maulik et al. 2002); moreover, HGF has been shown to regulate many processes involved in tumorigenesis (e.g., cell cycle control, invasion, motility, apoptosis, angiogenesis, and branching morphogenesis; Maulik et al. 2002). Although a description of the involvement of the HGF/c-met system in oncogenesis is beyond the scope of this review, the fact that HGF can mediate many of these mechanisms in (healthy) growing follicles, as well as tumor cells, is compelling. Future studies which reveal how the normal and pathologic processes which are regulated by HGF compare at the molecular level are likely to be beneficial for furthering our understanding of how timed cycles of growth, differentiation, injury, and repair switch from normal to an oncogenic course. The remaining discussion of ovarian function describes what is currently known about the role of the HGF/c-met system during normal follicle development.
Both HGF and c-met are expressed within mammalian ovaries as has been shown in the human, rat, pig, cow, and mouse (Liu et al. 1994, Parrott et al. 1994, Parrott & Skinner 1998a, Osuga et al. 1999, Shimizu et al. 2003). Importantly, intraovarian HGF is an autocrine/paracrine regulator of GC and theca cell growth and steroidogenesis (Zachow et al. 1997, 2000, Lail-Trecker et al. 1998, Parrott & Skinner 1998b, Zachow & Woolery 2002).
The cellular localization of HGF within the mammalian ovary was first demonstrated by Parrott et al. (1994). This study showed that HGF mRNA and protein were present within bovine theca cells; whereas, HGF was not detected within bovine GC. Moreover, in bovine GC in vitro, HGF induced cell proliferation, but did not induce theca cell growth (Parrott et al. 1994). This established the basic mesenchymal-epithelial cell model for HGF bioactivity (described above) within the mammalian ovary. Subsequent studies demonstrated that in addition to theca cells, HGF 1) is expressed within GC and 2) can modulate both theca cell and GC function, as described below.
Theca cells
The steroid modulatory effects of HGF were first demonstrated using primary cultures of theca-interstitial cells from sexually immature rats. In rat theca cells in vitro, HGF suppressed LH-dependent androsterone secretion, while also blocking the steady-state level of CYP17 expression (Zachow et al. 1997). Basal and LH-induced progesterone production were stimulated in the presence of HGF; but neither the expression of CYP11A nor 3ß-hydroxysteroid dehydrogenase was affected by HGF (Zachow et al. 1997). Although steroidogenesis was modulated by HGF, DNA content in rat theca cell cultures was not altered, suggesting that HGF did not stimulate proliferation of these cells. Using quantitative RT-PCR, this same study also demonstrated that, in the immature rat, HGF mRNA was expressed in both theca cells and GCs (Zachow et al. 1997). Therefore, in contrast to what was observed in the cow (Parrott et al. 1994), in the immature rat, HGF is expressed within both follicle cell populations.
The direct effect of HGF on theca cell function was questioned early on, in fact it was postulated that the HGF-correlated regulation of theca cell steroidogenesis was indirect; that is, due to actions of HGF in contaminating GC within theca cell cultures, which secreted steroid regulatory factors (Lail-Trecker et al. 1998). More recent data support the initial model reported by Zachow et al. (1997) suggesting a direct effect of HGF on theca cell function. Specifically, as shown by Uzumcu et al. (2006) the in vivo priming of immature rats with equine chorionic gonadotropin (eCG; to induce the growth of mature preovulatory follicles) resulted in elevated HGF and c-met immunoreactive proteins within the theca cells of large antral follicles. Also, c-met expression has been detected in human theca cells (Ito et al. 2001). Furthermore, in human chorionic gonadotropin (hCG)-primed gilts, c-met mRNA is expressed within theca cells (Shimizu et al. 2003). Thus, experimental evidence shows that both HGF and c-met are produced by theca cells as well as GC. Moreover, theca cells are likely respond to direct stimulation by HGF with changes in steroidogenic gene expression leading to alterations in androgen and progesterone production (Zachow et al. 1997).
The effects of HGF within theca cells are not restricted to the modulation of steroidogenesis. As shown by Parrot et al. in bovine theca cells in vitro, hCG stimulated the production of HGF (Parrott & Skinner 1998b). This initiated a paracrine feedback loop whereby theca-derived HGF promoted the secretion of kit ligand from GC. Kit ligand in turn 1) upregulated the production of HGF within theca cells and 2) induced theca cell proliferation (Parrott & Skinner 1998b, 2000). An essentially identical HGF-kit ligand system was also demonstrated in human theca cells and GC in vitro (Ito et al. 2001).
The presence of ovarian HGFA has been reported (Uzumcu et al. 2006); recall that HGFA represents a potential control mechanism for regulating local bioactive HGF concentrations. As first published by Uzumcu et al. (2006), in non-primed rat ovaries, a somewhat uniform HGFA signal was observed in GC within, and theca cells surrounding, preantral follicles; however, immunoreactive HGFA was not detected in oocytes. The same general pattern of HGFA was apparent within the antral follicles contained within these ovaries. In the ovaries of eCG-primed immature rats, a more intense signal for HGFA was present in theca cells when compared with that detected within GC. This pattern for HGFA was especially apparent in the theca cells associated with large antral follicles. The GC within large antral follicles showed no immunoreactive HGFA (Uzumcu et al. 2006).
Granulosa cells
Expression of the HGF system The proliferation and steroidogenic differentiation of GC into estrogenic and ultimately progestagenic cells is vital for reproductive function. Since the control of GC differentiation into steroidogenic cells is critical for maintaining female reproductive viability, any factor which modulates GC function is of potential importance in this context. The first studies showing an effect of HGF within the ovary were conducted by Parrott et al. (1994) in which HGF induced proliferation of bovine GC in vitro. This indicated that GC contain functional c-met, and this was indeed established shortly thereafter when the expression of c-met mRNA was identified in mouse GC (Yang & Park 1995). Subsequently, it was demonstrated that FSH and HGF each reduced c-met expression in rat GC in vitro (Zachow et al. 2000). Whereas, the cAMP analog, dibutyryl-cAMP, increased the level of c-met mRNA in cultured rat GC (Zachow et al. 2000). This was a compelling set of observations since FSH stimulates a profound increase in cAMP production in GC; hence, at a first approximation, these data showing changes in the level of c-met expression appeared paradoxical. One explanation for these observations is that FSH mobilizes a variety of signaling molecules, and crosstalk between cAMP-mediated and non-cAMP-mediated signaling cascades could control c-met content in GC.
Further studies investigating the regulation of ovarian c-met content were conducted by Uzumcu et al. (2006). As reported by these authors using ovaries harvested from immature rats, immunoreactive c-met staining was the most intense in GC within small preantral follicles; however, following eCG priming of immature rats (to induce the growth of large antral follicles), there was a shift in c-met intensity which resulted in relatively low c-met levels in GC, but relatively high c-met content in theca cells surrounding large antral follicles (Uzumcu et al. 2006).
The early report by Parrott et al. (1994) by-and-large strengthened the belief that HGF worked via the basic mesenchymal-epithelial mechanism of action that was proposed following its identification in epithelial cell cultures (Bussolino et al. 1992). However, subsequent studies challenged this model by showing that human, rat, and pig GC not only express c-met, but also contain HGF (Zachow et al. 1997, Osuga et al. 1999, Shimizu et al. 2003, Uzumcu et al. 2006). In the rat, eCG priming induced a reduction in immunoreactive HGF in GC, while increasing the HGF signal in theca cells of large antral follicles (Uzumcu et al. 2006). It is therefore important to consider that HGF is not expressed in theca cells and GC alone, but the level of ovarian HGF is subject to hormonal regulation in vivo (Uzumcu et al. 2006).
HGF and GC steroidogenesis Since a HGF system has been localized within the ovary, it is not surprising that HGF affects several key aspects of GC function as has been shown by numerous in vitro studies. In GC obtained from human in vitro fertilization (IVF) patients, HGF stimulated progesterone production (Ito et al. 2001). In contrast, in the rat HGF did not alter FSH-stimulated progesterone production, nor that induced by combined treatment with FSH and IGF-I in GC cultures (Zachow & Woolery 2002). Whereas in bovine GC, HGF suppressed hCG-supported progesterone synthesis (Parrott & Skinner 1998a). Therefore, depending upon the species, and perhaps the state of follicle differentiation, HGF can cause changes in progesterone production, and may thus exert control over luteogenesis and/or corpus luteum function.
One hallmark feature of folliculogenesis is the steroidogenic differentiation of theca cells and GC which appears to occur sometime during late the preantral or early antral phases of follicle growth. Within GC, theca cell androgens are aromatized into estrone (E1), which is subsequently converted into E2 by 17ß-HSD type 1. Through this cooperation, the GCs within preovulatory follicles account for the majority of the preovulatory rise in serum E2; and these changes in serum E2 lead to the pattern of gonadotropin secretion which enables ovulation. Although the steroidogenic differentiation process is held in check in small preantral follicles in vivo, GC harvested from preantral follicles will produce copious amounts of E2 when challenged with FSH or cAMP analogs (in the presence of aromatizable androgens) in vitro (Erickson 1983). Likewise, theca cells obtained from sexually immature rat ovaries will secrete substantial quantities of androgen in the presence of LH in vitro (Erickson 1983). Thus, it appears that the GC and theca cells in immature follicles, which do not produce appreciable amounts of androgens and E2 in vivo, have an abundant steroidogenic capacity when removed from the in vivo milieu. These observations have led to the development of a model suggesting that one or more factors within the follicular microenvironment most likely restrain E2 production in less immature (preantral) GC by directly impairing CYP19 and/or blocking the production of theca cell androgens. Although some of these factors, such as growth differentiation factor-9 and bone morphogenetic protein-15 are produced and secreted by oocytes (Vitt et al. 2000, Matzuk et al. 2002, McNatty et al. 2005), somatic cell-derived factors, including HGF, regulate follicular cell proliferation, differentiation, and steroidogenesis. This notion is supported by the fact that many intraovarian growth factors have been identified, including HGF, which modulate both FSH-directed E2 synthesis in GC and LH-supported androgen production in theca cells (Magoffin 1991, Terranova 1991).
As shown by Zachow et al. in immature rat GC in vitro, HGF blocked E2 production that was stimulated by FSH and FSH in the presence of IGF-I (Zachow & Woolery 2002). Interestingly, while HGF did not suppress FSH-stimulated E1 production in rat GC, HGF did block the aromatization of androstenedione into E1 which is promoted by FSH and IGF-I (Zachow & Woolery 2002). These effects were correlated to changes in CYP19 expression and activity, as well as modulation of the level of 17ß-HSD type 1 mRNA; indicating that, dependent upon the hormonal milieu, HGF can block the metabolism of androstenedione at one or more loci within the estrogenic pathway (Parrott & Skinner 1998a, Zachow et al. 2000).
A recent and interesting observation supported the above evidence that HGF suppresses E2 production in immature follicles. In GC harvested from human follicles from non-IVF patients, HGF impaired E2 production in GC isolated from small diameter preantral follicles. Whereas, HGF did not significantly impair FSH-dependent E2 production in GC harvested from the larger, antral human follicles (Zachow unpublished observations; Fig. 1). This indicates that the suppressive effects of HGF are sensitive to the state of GC maturation since different effects were detected in GC from small versus large diameter follicles. In addition, in the GC that were harvested from younger follicles, HGF did not impair E2 production in the presence of the highest dose of FSH tested (Fig. 1). One interpretation of these observations is that HGF dampens E2 synthesis in immature GC (i.e., those harvested from immature follicles); however, as GC mature (i.e., those harvested from large diameter follicles), and as FSH concentrations rise, yet-to-be defined mechanisms impair the ability of HGF to attenuate FSH-directed E2 production in GC. One plausible candidate for this downregulatory effect is at level of c-met content in GC, since FSH, HGF, and eCG each down-modulated c-met mRNA or protein in vivo and in GC cultures as described above (Zachow et al. 2000, Uzumcu et al. 2006). These observations further support the hypothesis that a developmental switch, perhaps at the level of c-met expression, occurs in GC which overcomes or prevents the suppressive effect of HGF on E2 secretion. This concept also fits within the physiologic context of what occurs during folliculogenesis in vivo (i.e., a switch from non-estrogenic to estrogenic GC); and the identification of HGF as a modulator of this intricate and tightly regulated process is compelling.
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In addition to its modulatory actions on E2 and progesterone production, HGF blocks apoptosis in cultured rat follicles and isolated immature rat GC (Uzumcu et al. 2006). Although not linked within the same study, it was discovered that HGF caused biphasic increases in the steady-state level of Akt1 mRNA, and as described above, HGF increased cGMP content in GC (Zachow et al. 2000, Zachow & Woolery 2002). This is potentially significant in that the activation of PI-3K/Akt- and cGMP-dependent signaling mechanisms block apoptosis in GC (Westfall et al. 2001, Peluso & Pappalardo 2004). Collectively, these findings imply that the anti-apoptotic effect of HGF within GC may be mediated by the induction of PI-3K/Akt and/or cGMP-dependent signal transduction. A review of some signaling mechanisms that are used by HGF is presented in Fig. 2.
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The testis
Many parallel mechanisms exist when comparing ovarian and testicular function. Like the ovary, the testis comprises distinct cell populations which work in concert to control fertility. Testicular cells include germ cells, as well as Leydig and Sertoli cells. Leydig and Sertoli cells respond to LH and FSH respectively, to produce androgens (testosterone), E2, several growth factors, and cytokines which control testicular differentiation and function (Bornstein et al. 2004, Haider 2004, Rao 2005, Itman et al. 2006, Mackay & Smith 2007).
The precise function of testicular E2 remains debatable, and has been thoroughly reviewed elsewhere (Sierens et al. 2005, Carreau et al. 2006). However, through the collective production of testosterone, several growth factors (including HGF), and other proteins, Leydig and Sertoli cells (like ovarian theca cells and GC) cooperate to support germ cell maturation, and are thus vital for male reproductive health.
In addition to Sertoli and Leydig cells, peritubular myoid cells represent another somatic cell type which is involved in epithelial-mesenchymal interactions within the testis. During embryonic gonadal development, peritubular myoid cells differentiate from cells that migrate from neighboring mesonephros, which is essential for normal testicular cord formation (Tilmann & Capel 1999). During postnatal life, peritubular myoid cells provide normal tubule morphology and contractility, processes that are critical for spermatogenesis (Zhang et al. 2006). Peritubular myoid cells and Sertoli cells interact with each other through growth factor-mediated feedback; these cells collaborate to produce extracellular matrix components which comprise the basement membrane that separates these two cell types (Skinner et al. 1985, Skinner 1991).
The ontogeny of HGF and c-met expression during testicular development
As with the ovary, the testis contains an endogenous HGF system, with a pattern of expression for HGF and c-met which is species specific. Although there are no published reports to date showing the ontogeny of HGF and/or c-met expression during ovarian development, changes in HGF and c-met expression during embryonic and postnatal testicular development have been described (Catizone et al. 1999, 2005, Ricci et al. 1999, 2002, 2006).
HGF expression starts in the mesonephros and coelomic epithelium of the undifferentiated male urogenital ridge as early as 11.5 day post-coitum (dpc) in the mouse (Ricci et al. 2002), and remains within the interstitium (presumably in peritubular myoid cells). Although c-met is first expressed inside the cords starting on 12.5 dpc, it is not clear at this time whether c-met is expressed by Sertoli or germ cells within cords. However, based on the classical paracrine model proposed for the HGF/c-met system (suggesting that HGF is produced by mesenchymal cells and acts on epithelial cells), Sertoli cells are the likely target for HGF within the cords. Ricci et al. (2006) reported that in the mouse at 13.5 and 15.5 dpc, c-met was mainly present within the testicular cords, and by 18.5 dpc, c-met was more localized to the interstitium (presumably fetal Leydig cells) and is no longer expressed in the cords (Table 2).
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In contrast to the diverse palate of regulatory functions which have been shown for HGF within ovarian follicle cells, within the testis, HGF bioactivity appears to be relatively more specific to critical morphogenic effects during embryonic and postnatal development (Catizone et al. 2001, 2002, 2005, 2006, Ricci et al. 2006). Noteworthy is the observation that germ cells express c-met in human and rat testes (Depuydt et al. 1996, Catizone et al. 2006). Interestingly, using the adenoviral-mediated overexpression and a postnatal testis tissue culture system, HGF was shown to block apoptosis and stimulate proliferation of germ cells in the rat testis (Goda et al. 2004, Catizone et al. 2006). These findings show similarities with the proposed anti-apoptotic function of HGF within ovarian GC described above (Uzumcu et al. 2006). If such an effect occurs under normal conditions in vivo, this would indicate an essential role of the intratesticular HGF system in controlling male fertility by affecting fetal testicular development and adult testicular function.
We propose that another similarity may exist between the roles of the HGF system in the ovary and the testis if it is found that HGF controls prepubertal E2 production in Sertoli cells. To elaborate, HGF and c-met are not expressed in Sertoli cells on postnatal day 10 (Catizone et al. 1999, 2001) when Sertoli cells are capable of producing a greater quantity of E2 (Le Margueresse & Jegou 1988). Whereas on postnatal day 25, Sertoli cells first show the expression of HGF and c-met (Catizone et al. 2001, 2005); interestingly, this is the time when E2 production by Sertoli cells is reduced (Le Margueresse & Jegou 1988). Since the HGF-dependent suppression of E2 was observed in rodent and human GC, it is plausible that HGF may control this aspect of the Sertoli differentiation; a novel mechanism which is worth further investigation.
HGF and Sertoli cells
In response to FSH, testosterone, and growth factors, Sertoli cells maintain a microenvironment that is conducive for spermatogenesis (Griswold 1998, Huleihel & Lunenfeld 2004, Walker & Cheng 2005). During embryonic life, sex-determining region of Y chromosome (Sry) expression initiates Sertoli cell differentiation leading to testis development (Sinclair et al. 1990). Paracrine growth factors expressed in the differentiating testis mediate the action of Sry. For example, FGF-9 exerts a significant role in critical cellular events during testis differentiation, such as mesonephric cell migration, Sertoli cell proliferation, and ultimately cord formation (Schmahl et al. 2004). In the absence of FGF-9, testicular abnormalities ranging from testicular hypoplasia to sex reversal occur in XY (i.e., genetically male) embryos (Colvin et al. 2001). Platelet-derived growth factors (PDGFs; Colvin et al. 2001, Uzumcu et al. 2002b, Brennan et al. 2003) constitute another group of paracrine growth factors which function in Leydig cell differentiation as well as other cellular events downstream from Sry activation (Brennan et al. 2003). The inhibition of PDGF bioactivity or deletion of PDGFR- causes abnormal cord formation (Uzumcu et al. 2002b, Brennan et al. 2003).
Additional paracrine factors with important functions in the developing testis are neurotrophins (Cupp et al. 2000, Levine et al. 2000), TGF-ß (Cupp et al. 1999), VEGF (Bott et al. 2006), kit ligand (Vincent et al. 1998), and glial cell line-derived neurotropic factor (GDNF; Meng et al. 2000). The roles of these growth factors in promoting testicular differentiation and development have been extensively reviewed elsewhere (Brennan & Capel 2004, Mackay & Smith 2007).
HGF is somewhat unique among growth factors. Unlike the growth factors mentioned above that are mainly products of Sertoli cells (an epithelial cell type) and act on mesenchymal cells, HGF is primarily produced by myoid cells (a mesenchymal cell type), especially during embryonic development. Thus, when considering communication between Sertoli and myoid cells, HGF represents an interesting growth factor because it mostly acts in the mesenchymal-to-epithelial direction. The identification of c-met within Sertoli cells enforces the validity of this model.
The pattern of c-met expression within the cords during embryonic life is not exactly known, but beginning sometime between postnatal days 20-25 (in the rat), Sertoli cells contain functional c-met protein (Catizone et al. 2001). In dissociated rat Sertoli cells in vitro, the administration of exogenous HGF induces the formation of structures resembling testicular seminiferous cords (Catizone et al. 2001). This experimental observation led to the notion that HGF may be instrumental in testicular lumen formation in mature animals (Catizone et al. 2001). It is also imperative to consider that testicular cord formation is a major morphologic event during embryonic gonad development in the male (Uzumcu et al. 2002a,b). This process requires Sertoli cell growth and differentiation, as well as mesonephric cell migration (reviewed in (Yao et al. 2002), changes which may be mediated by HGF (Ricci et al. 1999). Overall, the available evidence then suggests that HGF is one of several growth factors (including TGF-ß, FGF-9, PDGF, neurotrophins, GDNF, VEGF, and others) with an important role in development and function of the testis including cord formation and Sertoli cell differentiation.
HGF and myoid cells
It seems that HGF has two different modes of action depending upon the stage of development. Initially, during the embryonic developmental stage, the mode of action used by HGF is essentially paracrine. Thus, HGF from myoid cells targets cells inside the seminiferous cords (i.e., Sertoli cells and/or germ cells) between 12.5 and 15.5 dpc, and then acts on fetal Leydig cells on 18.5 dpc (Ricci et al. 1999, 2002, 2006). However, a switch occurs during postnatal developmental, when HGF activity becomes primarily autocrine, with some paracrine function still operational.
Both HGF and c-met are expressed in myoid cells prior to postnatal day 25. After day 25, the expression of HGF and c-met appears in Sertoli cells, while the expression of HGF and c-met in myoid cells is relatively subsided (Catizone et al. 1999, 2001, 2006). In addition to myoid and Sertoli cells, c-met mRNA is also present in germ cells between postnatal days 10 and 60 (Catizone et al. 2002, 2006), and in Leydig cells in adolescent rats (days 30-32; Del Bravo et al. 2007).
HGF and Leydig cells
The testicular correlate of the ovarian theca cell is the Leydig cell. As such, Leydig cells do not express FSH receptors, but do express LH receptors, and are stimulated by LH to produce testosterone as the predominant steroid. Beginning around fetal day 18.5, c-met is expressed within the mouse testicular interstitium; and organ culture of fetal day 18.5 testes revealed that HGF stimulated basal testosterone secretion (Ricci et al. 2006). Postnatal (days 30-32) rat Leydig cells also express immunoreactive c-met, and HGF stimulates basal testosterone secretion and inhibits apoptosis in rat Leydig cells as well as testicular tissue explants (Del Bravo et al. 2007).
Proposed regulatory function for HGF in the testis
What is apparent is that shifts in the expression of c-met and HGF between Sertoli cells, germ cells, Leydig cells, and myoid cells during fetal and postnatal testicular growth and differentiation suggest that HGF guides changes in testicular morphogenesis and function (including steroidogenesis) in a developmentally regulated manner. This type of model overlaps with that proposed for HGF during folliculogenesis. One hypothesis which can be derived from these data from the testis is that HGF promotes Sertoli cell differentiation and cord formation during in utero development, but then HGF control switches to the regulation of Leydig cell steroidogenic differentiation during the last stages of fetal development and preceding sexual maturity. Beginning around the time of puberty (i.e., day 25 in the rodent), Sertoli cells resume the expression of c-met (Table 2), and once again gain HGF responsiveness. It is possible that, in the prepubertal male, HGF controls Sertoli cell function at multiple levels, to potentially include the modulation of FSH-stimulated E2 production and cell growth; this, however, remains uncertain pending future studies. By regulating Sertoli cell function, HGF would indirectly control sperm growth and maturation, in addition to the direct effects of HGF on sperm function.
The stimulatory effect of HGF on steroid production in postnatal Leydig cells has recently been reported (Del Bravo et al. 2007). Based upon the most current data, HGF directly stimulates rat Leydig cell steroidogenesis, although mature human Leydig cells do not express c-met (Depuydt et al. 1996, Catizone et al. 2001). Considering that any effects of HGF are plausibly species specific, as has been documented with the ovarian HGF system, this difference is not surprising. What has been substantiated is that, collectively, the intratesticular HGF system has several potentially vital roles, those being the regulation of 1) seminiferous cord formation and development, 2) Leydig cell steroidogenesis and survival, 3) Sertoli cell proliferation and terminal differentiation, and 4) germ cell function and/or survival. To date, the ability of HGF to control testicular function in vivo (i.e., male reproductive viability) has not been reported. Considering that the either HGF or c-met null mutations are embryonic lethal (as described above), a tissue-specific conditional knockout approach is needed to establish the importance of the HGF system in regulating testis development and function in vivo.
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Received in final form 11 September 2007
Accepted 13 September 2007
Made available online as an Accepted Preprint 13 September 2007
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