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Abstract

A role for kit receptor signaling in Leydig cell steroidogenesis (PDF) (HTML) 
Rothschild,Gerson; Sottas,Chantal M.; Kissel,Holger; Agosti,Valter; Manova,Katia; Hardy,Matthew P.; Besmer,Peter
Biology of Reproduction 69(3): 925-932
Publication date: 2003

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Kit and its ligand, Kitl, function in hematopoiesis, melanogenesis,and gametogenesis. In the testis, Kitl is expressed by Sertolicells and Kit is expressed by spermatogonia and Leydig cells.Kit functions are mediated by receptor autophosphorylation andsubsequent association with signaling molecules, including phosphoinositide(PI) 3-kinase. We previously characterized the reproductiveconsequences of blocking Kit-mediated PI 3-kinase activationin Kit/Kit knockin mutant male mice. Only gametogenesiswas affected in these mice, and males are sterile because ofa block in spermatogenesis during the spermatogonial stages.In the present study, we investigated effects of the Kitmutation on Leydig cell development and steroidogenic function.Although the seminiferous tubules in testes of mutant animalsare depleted of germ cells, the testes contain normal numbersof Leydig cells and the Leydig cells in these animals appearto have undergone normal differentiation. Evaluation of steroidogenesisin mutant animals indicates that testosterone levels are notsignificantly reduced in the periphery but that LH levels areincreased 5-fold, implying an impairment of steroidogenesisin the mutant animals. Therefore, a role for Kit signaling insteroidogenesis in Leydig cells was sought in vitro. PurifiedLeydig cells from C57Bl6/J male mice were incubated with Kitl,and testosterone production was measured. Kitl-stimulated testosteroneproduction was 2-fold higher than that in untreated controls.The Kitl-mediated testosterone biosynthesis in Leydig cellsis PI 3-kinase dependent. In vitro, Leydig cells from mutantmice were steroidogenically more competent in response to LHthan were normal Leydig cells. In contrast, Kitl-mediated testosteroneproduction in these cells was comparable to that in normal cells.Because LH levels in mutant males are elevated and LH is knownto stimulate testosterone biosynthesis, we proposed a modelin which serum testosterone levels are controlled by elevatedLH secretion. Leydig cells of mutant males, unable to respondeffectively to Kitl stimulation, initially produce lower levelsof testosterone, reducing testosterone negative feedback onthe hypothalamic-pituitary axis. The consequent secretion ofadditional LH, under this hypothesis, causes a restoration ofnormal levels of serum testosterone. Kitl, acting via PI 3-kinase,is a paracrine regulator of Leydig cell steroidogenic functionin vivo.

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