Receptors for anti-Müllerian hormone on Leydig cells are responsible for its effects on steroidogenesis and cell differentiation

Abstract

Strong overexpression of anti-Müllerian hormone (AMH) in transgenic mice leads to incomplete fetal virilization and decreased serum testosterone in the adult. Conversely, AMH-deficient mice exhibit Leydig cell hyperplasia. To probe the mechanism of action of AMH on Leydig cell steroidogenesis, we have studied the expression of mRNA for steroidogenic proteins in vivo and in vitro and performed a morphometric analysis of testicular tissue in mice overexpressing the hormone. We show that overexpression of AMH in male transgenic mice blocks the differentiation of Leydig cell precursors. Expression of steroidogenic protein mRNAs, mainly cytochrome P450 17␣-hydroxylase͞C17-20 lyase (P450c17), is decreased in transgenic mice overexpressing AMH and in AMH-treated purified Leydig cells. In contrast, transgenic mice in whom the AMH locus has been disrupted show increased expression of P450c17. In vitro, but not in vivo, AMH also decreases the expression of the luteinizing hormone receptor. The effect of AMH is explained by the presence of its receptor on Leydig cells. Our results provide insight into the action of AMH as a negative modulator of Leydig cell differentiation and function.

Expression levels of Mullerian-inhibiting substance, GATA4 and 17alpha-hydroxylase/17,20-lyase cytochrome P450 during embryonic gonadal development in two diverse breeds of swine

“…Similarly, increased P450 c17 with age is consistent with the requirement for testosterone production from the testis for maintenance of Wolffian ducts and subsequent development of male genitalia. In addition to the vital role of MIS on the Mullerian ducts, MIS has been implicated as a negative modulator of Leydig cell differentiation and function (Behringer et al 1990, Mishina et al 1996, Racine et al 1998. However, the profiles of MIS and P450 c17 protein in the present study do not support a role for MIS as a negative regulator of P450 c17 expression in the embryonic pig.…”

Expression of anti-Müllerian hormone and its type II receptor in germ cells of maturing rat testis

“…Expression of Amhr2 in the rat Leydig cells has been observed in postnatal day 13 [19]. Male transgenic mice overexpressing Amh manifest feminized genitalia [20], in accordance with the decrease in Leydig cell numbers and testosterone secretion [18]. Conversely, Amh knockout mice manifest Leydig cell hyperplasia and infertility [8,21].…”

“…Changes in expression of Ngfr and Rhox5 during testis maturation indicate those in the population of immature and mature Sertoli cells. AMH produced by the immature Sertoli cells negatively regulates the adult Leydig cell-differentiation [18]. Expression of Amhr2 in the rat Leydig cells has been observed in postnatal day 13 [19].…”

Key factors in the regulation of fetal and postnatal leydig cell development

“…MIS also has critical paracrine roles in regulating fetal androgen production and postnatal Leydig cell biosynthesis and development (Racine et al, 1998;Lee et al, 1999;Teixeira et al, 1999;Salva et al, 2001;Sriraman et al, 2001;Wu et al, 2005). MIS may also coordinate commitment to the Leydig cell lineage and stimulate progenitor Leydig cell differentiation as overexpression of human MIS in a transgenic mouse model blocked the differentiation of the mesenchymal stem cells (Racine et al, 1998) and deletion of the MIS type II receptor resulted in an immature pattern of androgen production (Wu et al, 2005). In the mice with a targeted deletion of the MIS receptor, although Leydig cells were less differentiated, they were also increased in number.…”