DEVELOPMENTAL CONTROL OF LEYDIG AND SERTOLI CELLS BY MIS

转化生长因子-β家族成员--苗勒氏抑制物质 在生长和分化因素中，具有至关重要的作用 男性胚胎性分化引起的退缩 苗勒管，女性内部生殖道的原基。 意想不到的间质细胞增生和肿瘤表型 靶向缺失的小鼠的心肌梗死或其受体， 然而，提出了管理信息系统在发展中的新角色的前景 睾丸。这些数据表明，管理信息系统在帮助 维持大脑中支持细胞和间质细胞的正常补充 成熟的睾丸。这项提议将检验这样一种假设，即 防止未成熟的间质细胞无节制地增殖和 在成熟细胞中调节它们对有丝分裂因子的反应性 睾丸。这项建议的具体目的是：1.描述一下 MISII型受体在支持细胞和间质细胞中的表达 验证管理信息系统在这些单元中发出信号的能力，并检查 小鼠间质细胞和支持细胞体外抗增殖作用 有助于阐明荷尔蒙影响对疾病控制的相互作用 发育中的睾丸细胞增殖。2.)描绘出 睾丸组织的表型(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 评估细胞增殖，并检测其抗增殖活性 在这些动物模型中，MIS3.)研究分子 丹参素抑制间质细胞增殖的机制 确定管理信息系统是否会导致细胞周期停滞或细胞凋亡 死亡。 这些研究旨在阐明管理信息系统的旁分泌和自分泌作用 在发育过程中，间质细胞和支持细胞将促进我们对 一种控制细胞增殖的新途径 出生后的睾丸。越来越多的增殖抑制物被 被认为在反击……行动中具有关键作用 有丝分裂促进剂，以实现组织生长和形态发生的平衡。 因此，马兜铃酸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 对于正常的性别分化和达到 二次性成熟和生殖能力。此外， 阐明管理信息系统阻止非调控细胞的途径 间质细胞的增殖和肿瘤转化将提供 对睾丸肿瘤发生机制的洞察。

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.