DEVELOPMENTAL CONTROL OF LEYDIG AND SERTOLI CELLS BY MIS

MIS 对间质细胞和支持细胞的发育控制

基本信息

批准号：
6526336
负责人：
Mary Min-chin Lee
金额：
$ 10.78万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2004-08-31
项目状态：
已结题

项目摘要

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.

苗勒管抑制物质 (MIS)，TGF-β 家族成员生长和分化因子，在生长过程中具有重要作用雄性胚胎性分化引起的复旧苗勒氏管，女性内生殖道的原基。间质细胞增生和肿瘤的意外表型定向删除 MIS 或其受体基因的小鼠，然而，提出了管理信息系统在发展中国家中发挥新作用的前景。睾丸。这些数据表明 MIS 在帮助维持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 的假设防止未成熟 Leydig 细胞的无限制增殖，调节它们对成熟过程中促有丝分裂因子的反应睾丸。该提案的具体目标是： 1.) 描述支持细胞和间质细胞中 MIS II 型受体的表达验证 MIS 在这些细胞中发出信号的能力，并检查 MIS 对原代 Leydig 和 Sertoli 细胞的抗增殖作用帮助阐明荷尔蒙对控制的相互作用发育中的睾丸中的细胞增殖。 2.) 描绘 MIS 的睾丸表型（细胞数量和分化功能）体视学研究和体内转基因和基因敲除小鼠评估增殖并检查抗增殖活性 MIS 在这些动物模型中的作用，以及 3.) 研究分子 MIS 抑制 Leydig 细胞增殖的机制确定 MIS 是否导致细胞周期停滞或细胞凋亡死亡。这些研究阐明了 MIS 的旁分泌和自分泌作用开发 Leydig 和 Sertoli 细胞将增进我们的理解控制细胞增殖的新途径产后睾丸。扩散抑制剂越来越多地被被认为在反击以下行为方面发挥着关键作用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形态发生和功能；流程对于正常的性别分化和获得性能力至关重要第二性成熟和生殖力。而且，澄清 MIS 防止细胞失控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。