Expression and functional role of hepatocyte growth factor and its receptor (c-met) during fetal mouse testis development

Abstract

The hepatocyte growth factor (HGF) is a pleiotropic cytokine able to regulate different cellular functions. HGF action is mediated by its receptor, c-met, a glycoprotein with tyrosine kinase activity. We previously demonstrated that c-met is expressed in the newly formed seminiferous cords of the mice embryonic testes and that HGF acts as a morphogenetic factor. In this paper, we report that at 15 . 5 days post-coitum (dpc) c-met is expressed in the testicular cords, whereas at 18 . 5 dpc c-met expression is almost exclusively localized in the interstitial tissue of the testis in particular in the fetal Leydig cells. In addition, we demonstrate that HGF gene is expressed during the fetal period of testis development, heavily detectable in the interstitial compartment of 18 . 5 dpc testes. Interestingly, HGF is not expressed in the Leydig cells that, as above reported, express the HGF receptor. Looking for the functional role of HGF on Leydig cells, we evaluated the amount of testosterone secreted by testes isolated from 18 . 5 dpc embryos and cultured in the presence of HGF. The results of the in vitro organ culture show that, at this age, HGF increases the amount of testosterone secreted in the culture medium. On the contrary, HGF does not modulate the amount of testosterone secreted by testes isolated from 15 . 5 dpc embryos. In conclusion, we report that HGF is produced in the interstitial compartment of the developing testis but not by the Leydig cells. Conversely, the HGF receptor c-met is expressed in the Leydig cells and HGF modulates Leydig cell function during the late period of prenatal development.

Hepatocyte Growth Factor Is a Mouse Fetal Leydig Cell Terminal Differentiation Factor1

“…Hepatocyte growth factor 50 U/ml did not exert a significant increase in HGF IS A FLC TERMINAL DIFFERENTIATION FACTOR testosterone secretion. These data overlap with the results previously presented by our group [53] that found an increase of approximately 50% in the 100 U/ml HGF-treated samples over the control samples.…”

“…In this study, we provide evidence that the HGF is one of these growth factors. The C-MET/HGF system has a well-established morphogenetic role in the embryonic development of mouse male gonads [43,[50][51][52][53]. In addition, an increasing amount of evidence demonstrates the implication of the C-MET/HGF HGF IS A FLC TERMINAL DIFFERENTIATION FACTOR system in the physiology of postnatal male and female reproductive organs as well as in the regulation of their differentiation [43][44][45].…”

“…HGF is localized in the connective tissue of the interstitial compartment, but it is not expressed by FLCs. In addition, our in vitro data showed that HGF stimulates testosterone secretion in organ culture of late fetal testis and in primary cell culture of rat pubertal Leydig cells [53,54]. In the present study, the proliferation rate, apoptotic index, and differentiation of Leydig cells in a testicular organ culture of 17.5-dpc embryos were analyzed to clarify the physiological role of HGF in late testis organogenesis.…”

The hepatocyte growth factor system as a regulator of female and male gonadal function

“…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 .…”

Hepatocyte Growth Factor Exerts Promoting Functions on Murine Dental Papilla Cells

“…HGF is now recognized as a multifunctional growth factor capable of acting as a potent mitogen, morphogen, or motility factor in many organs and thus is involved in a variety of physiological processes, including tissue development and regeneration (15,18,19). HGF was found to be involved in bovine mammary gland development (20), retinal neovascularization (21), fetal lung development (22), branching morphogenesis of murine salivary glands (23), and fetal testis development as well as having a crucial role in the regulation of male fertility (24,25). Sonnenberg et al (26) revealed the pattern of gene expression for HGF and the HGF receptor, c-met, in the rat tooth germ, suggesting a role for HGF in epithelialmesenchymal interactions during tooth development.…”