Mullerian Inhibiting Substance Recruits ALK3 to Regulate Leydig Cell Differentiation
Document Type
Journal ArticlePublication Date
2012-10-01Keywords
Anti-Mullerian HormoneActivin Receptors
Leydig Cells
Cell Differentiation
Cell and Developmental Biology
Cell Biology
Endocrinology, Diabetes, and Metabolism
Metadata
Show full item recordAbstract
Mullerian inhibiting substance (MIS) not only induces Mullerian 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 Mullerian 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 (17betaHSD-III and 3betaHSD-VI) that are expressed in differentiated adult Leydig cells and increased expression of androgen-metabolizing enzymes (3alpha-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.Source
Endocrinology. 2012 Oct;153(10):4929-37. Epub 2012 Aug 7. Link to article on publisher's siteDOI
10.1210/en.2012-1168Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36059PubMed ID
22872577Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1210/en.2012-1168