DEVELOPMENTAL CONTROL OF LEYDIG AND SERTOLI CELLS BY MIS

苗勒管抑制物质（MIS），TGF-β家族成员 生长和分化的因素，具有至关重要的作用， 男性胚胎性分化引起退化的 苗勒管，女性内部生殖道的原基。 睾丸间质细胞增生和瘤形成的非预期表型 具有MIS或其受体基因的靶向缺失的小鼠， 然而，提出了一个新的作用，管理信息系统在发展的前景 睾丸这些数据表明，管理信息系统在帮助 维持睾丸支持细胞和间质细胞的正常补充， 成熟的睾丸 该提案将检验MIS 防止未成熟Leydig细胞的不受限制的增殖， 调节它们在成熟过程中对促有丝分裂因子的反应性， 睾丸 本提案的具体目标是：1）表征 MIS II型受体在支持细胞和间质细胞中的表达， 验证MIS在这些细胞中发出信号的能力，并检查 MIS在原代Leydig和Sertoli细胞中的抗增殖作用， 有助于阐明激素对控制 睾丸发育中的细胞增殖 2.）的情况。划定 MIS的睾丸表型（细胞数量和分化功能） 通过体视学研究和体内研究的转基因和敲除小鼠 评估增殖，并检查抗增殖活性 在这些动物模型中的MIS，和3.）调查分子 MIS抑制Leydig细胞增殖的机制， 确定MIS是否引起细胞周期停滞或细胞凋亡 死亡 这些研究旨在阐明MIS的旁分泌和自分泌作用 睾丸间质细胞和支持细胞的发展将促进我们对 一种新的控制细胞增殖的途径， 出生后睾丸 增殖抑制剂越来越多地被 被认为在对抗恐怖主义行为方面发挥着关键作用的 促有丝分裂剂，以实现平衡的组织生长和形态发生。 因此，MIS对睾丸体细胞的抗增殖作用 细胞可能有助于控制睾丸的形态发生和功能;过程 这对正常的性别分化和实现 次级性成熟和生殖生育力。 此外，委员会认为， 阐明了MIS阻止不受调节的细胞增殖的途径， 间质细胞的增殖和肿瘤转化将提供 深入了解睾丸肿瘤发生的发病机制。

Mullerian inhibiting substance (MIS), a member of the TGF-beta family of growth and differentiation factors, has the essential role during male embryonic sexual differentiation of causing involution of the Mullerian ducts, the anlagen of the female internal reproductive tracts. The unexpected phenotypes of Leydig cell hyperplasia and neoplasia in mice with targeted deletions of the genes for MIS or its receptor, however, raised the prospect of a novel role for MIS in the developing testis. These data suggested that MIS has an essential role in helping to maintain a normal complement of Sertoli and Leydig cells in the maturing testis. This proposal will test the hypothesis that MIS prevents the unrestrained proliferation of immature Leydig cells and modulates their responsiveness to mitogenic factors in the maturing testis. The Specific Aims of this proposal are to: 1.) Characterize the expression of the MIS type II receptor in Sertoli and Leydig cells to verify the ability of MIS to signal in these cells, and examine the anti-proliferative role of MIS in primary Leydig and Sertoli cells to help elucidate the interplay of hormonal influences on the control of cellular proliferation in the developing testis. 2.) Delineate the testicular phenotypes (cell numbers and differentiated function) of MIS transgenic and knockout mice by stereologic studies and in vivo assessment of proliferation, and examine the anti-proliferative activity of MIS in these animal models, and 3.) Investigate the molecular mechanisms by which MIS inhibits Leydig cell proliferation by determining whether MIS causes cell cycle arrest or apoptotic cell death. These studies to elucidate the paracrine and autocrine actions of MIS in developing Leydig and Sertoli cells will advance our understanding of a novel pathway for control of cellular proliferation in the postnatal testis. Inhibitors of proliferation are increasingly being recognized as having critical roles in counter-acting the actions of mitogenic agents to achieve balanced tissue growth and morphogenesis. Thus the anti-proliferative action of MIS on the testicular somatic cells may help control testicular morphogenesis and function; processes that are essential for normal sexual differentiation and attainment of secondary sexual maturation and reproductive fertility. Moreover, clarification of the pathway by which MIS prevents unregulated cellular proliferation and neoplastic transformation of Leydig cells will provide insights into the pathogenesis of testicular tumorigenesis.