Teixeira J, Maheswaran S, Donahoe P K
Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Endocr Rev. 2001 Oct;22(5):657-74. doi: 10.1210/edrv.22.5.0445.
Dr. Alfred Jost pioneered the field of reproductive endocrinology with his seminal observation that two hormones produced by the testes are required for the male embryo to develop a normal internal reproductive tract. T induces the Wolffian ducts to differentiate into epididymides, vasa deferens, and seminal vesicles. Müllerian inhibiting substance (MIS) causes regression of the Müllerian ducts, which in its absence would normally develop into the Fallopian tubes, uterus, and upper vagina as is observed in female embryos. This review will summarize our current understanding of molecular mechanisms underlying the function of MIS both as a fetal gonadal hormone that causes Müllerian duct regression and as an adult hormone, the roles for which are currently being investigated, i.e., inhibition of steroidogenesis, germ cell development, and cancer. We will also address the regulation of MIS expression as one of the first genes expressed after the commitment of the bipotential gonads to differentiate into testes under the influence of SRY, the gene on the sex-determining region of the Y chromosome. We will discuss what is known regarding MIS signal transduction, which as with other members of the TGFbeta family of growth and differentiation factors, occurs through a heteromeric complex of single transmembrane serine/threonine kinase receptors to effect downstream signaling events, including Smad, nuclear factor-kappaB, beta-catenin, and p16 activation. Finally, we will assess the clinical relevance of studying MIS in patients with persistent Müllerian duct syndrome and our efforts to determine the therapeutic value of MIS for patients with ovarian and other MIS receptor-expressing cancers.
阿尔弗雷德·约斯特博士开创了生殖内分泌学领域，他有一项具有开创性的观察结果，即睾丸产生的两种激素是男性胚胎发育出正常内部生殖道所必需的。睾酮诱导中肾管分化为附睾、输精管和精囊。苗勒管抑制物质（MIS）会导致苗勒管退化，若没有这种物质，苗勒管通常会发育成女性胚胎中可见的输卵管、子宫和上段阴道。本综述将总结我们目前对MIS功能的分子机制的理解，MIS既是一种导致苗勒管退化的胎儿性腺激素，也是一种成年激素，目前正在研究其作用，即对类固醇生成、生殖细胞发育和癌症的抑制作用。我们还将探讨MIS表达的调控，它是在Y染色体性别决定区域的基因SRY的影响下，双潜能性腺定向分化为睾丸后最早表达的基因之一。我们将讨论已知的MIS信号转导情况，与转化生长因子β家族的其他生长和分化因子成员一样，MIS信号转导是通过单跨膜丝氨酸/苏氨酸激酶受体的异源复合物来实现的，以影响下游信号事件，包括Smad、核因子κB、β-连环蛋白和p16激活。最后，我们将评估在持续性苗勒管综合征患者中研究MIS的临床相关性，以及我们为确定MIS对卵巢癌和其他表达MIS受体的癌症患者的治疗价值所做的努力。
