Role of Transforming Growth Factor-α and the Epidermal Growth Factor Receptor in Embryonic Rat Testis Development1

Abstract

Embryonic testis development requires the morphogenesis of cords and growth of all cell populations to allow organ formation. It is anticipated that coordination of the growth and differentiation of various cell types involves locally produced growth factors. The current study was an investigation of the hypothesis that transforming growth factor-alpha (TGF-alpha) is involved in regulating embryonic testis growth. TGF-alpha has previously been shown to function in the postnatal testis. TGF-alpha and other members of the epidermal growth factor (EGF) family act through the epidermal growth factor receptor (EGFR) to stimulate cell proliferation and tissue morphogenesis. To understand the potential actions of TGF-alpha in the embryonic testis, general cell proliferation was investigated. Characterization of cell proliferation in the rat testis throughout embryonic and postnatal development indicated that each cell type has a distinct pattern of proliferation. Germ cell growth was transiently suppressed around birth. Interstitial cell growth was high embryonically and decreased to low levels around birth. A low level of Sertoli cell proliferation was observed at the onset of testis cord formation. Sertoli cell proliferation in early embryonic development was low; the levels were high later in embryonic development and remained high until the onset of puberty. Both TGF-alpha and the EGFR were shown to be expressed in the embryonic and postnatal rat and mouse testis. Perturbation of TGF-alpha function using neutralizing antibodies to TGF-alpha on testis organ cultures dramatically inhibited the growth of both embryonic and neonatal testis. TGF-alpha antibodies had no effect on cord formation. The TGF-alpha antibody was found to be specific for TGF-alpha in Western blots when compared to EGF and heregulin. Testis growth was also inhibited by perturbation of EGFR signaling using an EGFR kinase inhibitor. Therefore, TGF-alpha appears to influence embryonic testis growth but not morphogenesis (i.e., cord formation). Treatment of embryonic testis organ cultures with exogenous TGF-alpha also perturbed development, leading to an increased proliferation of unorganized cells. Testis from EGFR and TGF-alpha knockout mice were analyzed for testis morphology. TGF-alpha knockout mice had no alterations in testis phenotype, while EGFR knockout mice had a transient decrease in the relative amount of interstitial cells before birth. Observations suggest that there may be alternate or compensatory factors that allow testis growth to occur in the apparent absence of TGF-alpha actions in the mutant mice. In summary, the results obtained suggest that TGF-alpha is an important factor in the regulation of embryonic testis growth, but other factors will also be involved in the process.

An epigenetic switch is crucial for spermatogonia to exit the undifferentiated state toward a Kit-positive identity

“…Scale bars: 100 μm in a,f; 50 μm in b-e,g-j. Kluin et al, 1984;Levine et al, 2000). Together, these data suggest that the influence of the Np95 cKO is restricted to germ cells in the testis.…”

Gonadotoropin actions on spermatogenesis and hormonal therapies for spermatogenic disorders [Review]

“…Most important, the influence of technology for female infertility treatment such as ICSI complicates the results of male infertility treatment (effect-modifying factor) [55]. spermatogenesis [38][39][40][41][42][43][44]. We found that transactivation of the EGF receptor (EGFR), a tyrosine kinase type receptor through the activation of LHR, a G protein coupled receptor, occurred both in MA-10 cells [45] and rat Leydig cell primary culture [46] after hCG stimulation.…”

Expression of vascular endothelial growth factor and transforming growth factor alpha in rat testis during chronic renal failure

“…TGF-a). [24] or neurotropin receptors such as low affinity neurotropin receptor (p75/LNGFR) [25]. However, besides the general knowledge that growth factors participate in different cellular compartments of the testis, little is known about the codistribution of TGF-a and VEGF in seminiferous tubuli.…”

“…Epidermal growth factor (EGF)/TGF-a is a family of growth factors that has attracted attention as putative regulators of embryonic [48] and testicular [24] development. Earlier results [49] supported by more recent findings [50] indicate that EGF/TGF-a family members are also directly involved in the regulation of spermatogenesis.…”