Genetic analysis of the Mullerian-inhibiting substance signal transduction pathway in mammalian sexual differentiation
Genetic analysis of the Mullerian-inhibiting substance signal transduction pathway in mammalian sexual differentiation
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DOI：
10.1101/gad.10.20.2577
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发表时间：
1996-10-15
影响因子：
10.5
通讯作者：
Behringer, RR
中科院分区：
文献类型：
--
作者：
Mishina, Y;Rey, R;Behringer, RR
苗勒氏抑制物质是转化生长因子-β基因家族的一员。男性的错配表达会导致米勒管的退化，这是男性性别分化的一个重要过程。最近，已分离到一个MISII型受体基因，该基因在胚胎发育过程中表达于苗勒管上皮附近的间充质细胞，以及胎儿和成人、男性和女性性腺的支持细胞和颗粒细胞中。MI受体突变的雄性发育为内部的假两性，拥有完整的雄性生殖道和子宫和输卵管，这是MIS配体缺陷雄性小鼠的表型。它们同时表达MISmRNA和蛋白，表明存在配基，但靶器官对激素不敏感。它们都能产生精子，但大多数都是不育的，因为它们的女性生殖器官的存在阻止了精子转移到女性体内。可观察到局灶性生精小管萎缩伴间质细胞增生，早在2个月龄就开始。MISL/MISR双突变雄鼠的表型与单突变体的表型无明显差异。MI受体/α-抑制素双突变男性发生睾丸间质瘤和大的充满液体的子宫，其表型与MISL/α-抑制素双突变男性相同。这些研究提供了体内证据，与其他转化生长因子-β基因家族信号通路的复杂性形成鲜明对比的是，管理信息系统是管理信息系统II型受体的唯一配基。
Mullerian-inhibiting substance (MIS) is a member of the transforming growth factor-beta (TGF-beta) gene family. MIS expression in males causes the regression of the Mullerian ducts, an essential process in male sexual differentiation. Recently, an MIS type II receptor gene has been isolated that is expressed during embryogenesis in mesenchymal cells adjacent to the Mullerian duct epithelium and in Sertoli and granulosa cells of the fetal and adult, male and female gonads, respectively. MIS receptor mutant males develop as internal pseudohermaphrodites, possessing a complete male reproductive tract and also a uterus and oviducts, a phenocopy of MIS ligand-deficient male mice. They express both MIS mRNA and protein, showing that ligand was present, but target organs were hormone-insensitive. All produce sperm, but the majority were infertile because the presence of their female reproductive organs blocks sperm transfer into females. Focal seminiferous tubule atrophy accompanied by Leydig cell hyperplasia was observed and began as early as 2 months of age. The phenotype of MIS ligand/MIS receptor double mutant males was indistinguishable from those of each single mutant. MIS receptor/alpha-inhibin double mutant males developed testicular stromal tumors and large fluid-filled uteri that were identical in phenotype to MIS ligand/alpha-inhibin double mutant males. These studies provide in vivo evidence that MIS is the only ligand of the MIS type II receptor, in contrast to the complexity of other TGF-beta gene family signaling pathways.