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ABSTRACT: Müllerian inhibiting substance (MIS) not only induces Müllerian duct regression during male sexual differentiation but also modulates Leydig cell steroidogenic capacity and differentiation. MIS actions are mediated through a complex of homologous receptors: a type II ligand-binding receptor [MIS type II receptor (MISRII)] and a tissue-specific type I receptor that initiates downstream signaling. The putative MIS type I receptors responsible for Müllerian duct regression are activin A type II receptor, type I [Acvr1/activin receptor-like kinase 2 (ALK2)], ALK3, and ALK6, but the one recruited by MIS in Leydig cells is unknown. To identify whether ALK3 is the specific type I receptor partner for MISRII in Leydig cells, we generated Leydig cell-specific ALK3 conditional knockout mice using a Cre-lox system and compared gene expression and steroidogenic capacity in Leydig cells of ALK3(fx/fx)Cyp17(cre+) and control mice (ALK3(fx/fx)Cyp17(cre-) or ALK3(fx/wt)Cyp17(cre-) littermates). We found reduced mRNA expression of the genes encoding P450c17, StAR, and two enzymes (17βHSD-III and 3βHSD-VI) that are expressed in differentiated adult Leydig cells and increased expression of androgen-metabolizing enzymes (3α-HSD and SRD5A2) and proliferating cell nuclear antigen (PCNA) in Leydig cells of ALK3(fx/fx)Cyp17(cre+) mice. Despite down-regulation of steroidogenic capacity in ALK3(fx/fx)Cyp17(cre+) mice, the loss of MIS signaling also stimulates Leydig cell proliferation such that plasma testosterone and androstenedione concentrations are comparable to that of control mice. Collectively, these results indicate that the phenotype in ALK3 conditional knockout mice is similar to that of the MIS-knockout mice, confirming that ALK3 is the primary type I receptor recruited by the MIS-MISRII complex during Leydig cell differentiation.
Endocrinology 08/2012; 153(10):4929-37. · 4.46 Impact Factor
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ABSTRACT: Postnatal Leydig cell (LC) development in mice has been assumed empirically to resemble that of rats, which have characteristic hormonal profiles at well-defined maturational stages. To characterize the changes in LC function and gene expression in mice, we examined reproductive hormone expression from birth to 180 days, and quantified in vivo and in vitro production of androgens during sexual maturation. Although the overall plasma androgen and LH profiles from birth through puberty were comparable to that of rats, the timing of developmental changes in androgen production and steroidogenic capacity of isolated LCs differed. In mice, onset of androgen biosynthetic capacity, distinguished by an acute rise in androstenedione and testosterone production and an increased expression of the steroidogenic enzymes, cytochrome P450 cholesterol side-chain cleavage enzyme and 17alpha-hydroxylase, occurred at day 24 (d24) rather than at d21 as reported in rats. Moreover, in contrast to persistently high testosterone production by pubertal and adult rat LCs, testosterone production was maximal at d45 in mice, and then declined in mature LCs. The murine LCs also respond more robustly to LH stimulation, with a greater increment in LH-stimulated testosterone production. Collectively, these data suggest that the mouse LC lineage has a delayed onset, and that it has an accelerated pace of maturation compared with the rat LC lineage. Across comparable maturational stages, LCs exhibit species-specific developmental changes in enzyme expression and capacity for androgen production. Our results demonstrate distinct differences in LC differentiation between mice and rats, and provide informative data for assessing reproductive phenotypes of recombinant mouse models.
Reproduction 05/2010; 140(1):113-21. · 2.58 Impact Factor
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ABSTRACT: Müllerian inhibiting substance (MIS), a secreted glycoprotein in the transforming growth factor-beta family of growth factors, mediates regression of the Müllerian ducts during embryonic sex differentiation in males. In persistent Müllerian duct syndrome (PMDS), rather than undergoing involution, the Müllerian ducts persist in males, giving rise to the uterus, fallopian tubes, and upper vagina. Genetic defects in MIS or its receptor (MISRII) have been identified in patients with PMDS. The phenotype in the canine model of PMDS derived from the miniature schnauzer breed is strikingly similar to that of human patients. In this model, PMDS is inherited as a sex-limited autosomal recessive trait. Previous studies indicated that a defect in the MIS receptor or its downstream signaling pathway was likely to be causative of the canine syndrome. In this study, the canine PMDS phenotype and clinical sequelae are described in detail. Affected and unaffected members of this pedigree are genotyped, identifying a single base pair substitution in MISRII that introduces a stop codon in exon 3. The homozygous mutation terminates translation at 80 amino acids, eliminating much of the extracellular domain and the entire transmembrane and intracellular signaling domains. Findings in this model could enable insights to be garnered from correlation of detailed clinical descriptions with molecular defects, which are not otherwise possible in the human syndrome.
Journal of Andrology 09/2008; 30(1):46-56. · 2.97 Impact Factor
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ABSTRACT: The primary function of testicular Leydig cells is the production of androgens to promote sexual differentiation in the fetus, secondary sexual maturation at puberty, and spermatogenesis in the adult. The fetal and postnatal (adult) populations of Leydig cells differ morphologically and have distinct profiles of gene expression. As postnatal Leydig cells differentiate, they transition through three discrete maturational stages characterized by decreasing proliferative rate and increasing testosterone biosynthetic capacity. In this review, we discuss the development of both fetal and postnatal Leydig cells and review the regulation of this process by some of the key hormones and growth factors.
Journal of Cellular Physiology 12/2007; 213(2):429-33. · 3.87 Impact Factor
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ABSTRACT: Mullerian inhibiting substance (MIS) causes Mullerian duct regression during sexual differentiation and regulates postnatal Leydig cell development. MIS knockout (MIS-KO) mice with targeted deletions of MIS develop Leydig cell hyperplasia, but their circulating androgen concentrations are reportedly unaltered. We compared reproductive hormone profiles, androgen biosynthesis, and the expression of key steroidogenic and metabolic enzymes in MIS-KO and wild-type (WT) mice at puberty (36 d) and sexual maturity (60 d). In pubertal animals, basal testosterone and LH concentrations in plasma were lower in MIS-KO than WT mice, whereas human chorionic gonadotropin-stimulated testosterone concentrations were similar. In adults, basal LH, and both basal and human chorionic gonadotropin (hCG)-stimulated testosterone concentrations were similar. Purified Leydig cells from pubertal MIS-KO mice had lower testosterone but higher androstanediol and androstenedione production rates. In contrast, testosterone, androstanediol, and androstenedione production rates were all lower in adult MIS-KO Leydig cells. Steroidogenic acute regulatory protein expression was lower in pubertal MIS-KO mice compared with WT, whereas 17beta-hydroxy-steroid dehydrogenase and 5alpha-reductase were greater, and P450c17 and P450scc were similar. The expression of steroidogenic acute regulatory protein and 17beta-hydroxysteroid dehydrogenase was lower in adult MIS-KO mice, whereas that of 5alpha-reductase, P450c17, and P450scc was similar. Collectively, these results suggest that in the absence of MIS, Leydig cells remain less differentiated, causing an altered intratesticular androgen milieu that may contribute to the infertility of MIS-KO mice. In immature mice, this deficit in steroidogenic capacity appears to be mediated by a direct loss of MIS action in Leydig cells as well as by indirect effects via the hypothalamic-pituitary-gonadal axis.
Endocrinology 02/2005; 146(2):589-95. · 4.46 Impact Factor
