Mullerian inhibiting substance signaling uses a bone morphogenetic protein (BMP)-like pathway mediated by ALK2 and induces Smad6 expression
Mullerian inhibiting substance signaling uses a bone morphogenetic protein (BMP)-like pathway mediated by ALK2 and induces Smad6 expression
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DOI：
10.1210/me.15.6.946
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发表时间：
2001-06-01
影响因子：
--
通讯作者：
Donahoe, PK
中科院分区：
文献类型：
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作者：
Clarke, TR;Hoshiya, Y;Donahoe, PK
苗勒管抑制物质（MIS）在男性胚胎苗勒管周围的间充质中的信号接收对于该管的退化是必不可少的。MIS或MIS II型受体（MISRII）的缺乏会导致雄性生殖发育异常，这是由于导管的维持。MIS是通过I型和II型丝氨酸/苏氨酸激酶受体的受体复合物发出信号的分泌蛋白激素的转化生长因子-β（TGF β）超家族的成员。为了研究候选MIS I型受体，我们检查了MIS对报告构建体的激活。骨形态发生蛋白（BMP）响应Tlx 2和Xvent 2启动子驱动的报告构建体刺激MIS，但TGF β/激活素诱导的p3 TP-lux或CAGA-luc报告构建体没有。Tlx 2-luc的诱导依赖于MISRII的激酶活性，并被显性负性截短的ALK 2（tALK 2）受体阻断，但不被其他BMP I型受体ALK 1、ALK 3或ALK 6的截短形式阻断。MIS诱导Gal 4DBD-Smad 1的活化，但不诱导Gal 4DBD-Smad 2融合蛋白的活化。这种激活也可以被tALK 2阻断。BMP诱导的抑制性Smad，Smad 6，上调MIS内源性Leydig细胞衍生的线，并在男性，但不是女性苗勒管间充质表达。已显示ALK 6作为MIS I型受体起作用。对发育中的泌尿生殖系统中ALK 2、MISRII和ALK 6模式的研究表明，ALK 2和MISRII在导管周围的间充质中重叠表达，而ALK 6仅在上皮中观察到。ALK 6-/-雄性动物的检查未发现导管退化缺陷。报告构建体分析、受体表达模式和ALK 6缺陷动物的分析表明ALK 2是参与苗勒管退化的MIS I型受体。
Signal reception of Mullerian inhibiting substance (MIS) in the mesenchyme around the embryonic Mullerian duct in the male is essential for regression of the duct. Deficiency of MIS or of the MIS type II receptor, MISRII, results in abnormal reproductive development in the male due to the maintenance of the duct. MIS is a member of the transforming growth factor-beta (TGF beta) superfamily of secreted protein hormones that signal through receptor complexes of type I and type II serine/threonine kinase receptors. To investigate candidate MIS type I receptors, we examined reporter construct activation by MIS. The bone morphogenetic protein (BMP)-responsive Tlx2 and Xvent2 promoter-driven reporter constructs were stimulated by MIS but the TGF beta /activin-induced p3TP-lux or CAGA-luc reporter constructs were not. The induction of Tlx2-luc was dependent upon the kinase activity of MISRII and was blocked by a dominant negative truncated ALK2 (tALK2) receptor but not by truncated forms of the other BMP type I receptors ALK1, ALK3, or ALK6. MIS induced activation of a Gal4DBD-Smad1 but not a Gal4DBD-Smad2 fusion protein. This activation could also be blocked by tALK2. The BMP-induced inhibitory Smad, Smad6, was up-regulated by MIS endogenously in Leydig cell-derived lines and is expressed in male but not female Mullerian duct mesenchyme. ALK6 has been shown to function as an MIS type I receptor. Investigation of the pattern of ALK2, MISRII, and ALK6 in the developing urogenital system demonstrated overlapping expression of ALK2 and MISRII in the mesenchyme surrounding the duct while ALK6 was observed only in the epithelium. Examination of ALK6-/- male animals revealed no defect in duct regression. The reporter construct analysis, pattern of expression of the receptors, and analysis of ALK6-deficient animals suggest that ALK2 is the MIS type I receptor involved in Mullerian duct regression.