Molecular function of Wnt/ß-Catenin signaling in the development of the ureteric mesenchyme in the mouse

Wnt/γ-Catenin 信号在小鼠输尿管间质发育中的分子功能

• 批准号: 171943101
• 负责人: Professor Dr. Andreas Kispert
• 金额: --
• 依托单位: Institut für Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/171943101?language=en
• 关键词: Molecular; function; Wnt; Catenin; signaling

Structural basis of the contractile activity of the ureter is an outer mesenchymal investment of smooth muscle cells and fibroelastic material that arises through a multi-step cellular program from an undifferentiated pool of mesenchymal precursor cells. Although congenital anomalies of the ureteric wall are frequent and may have deleterious consequences for renal function, little is known about the molecular circuits that orchestrate the development of the ureteric mesenchyme. In the first funding period we have shown that Wnt signals from the ureteric epithelium act via the canonical Ctnnb1-dependent pathway to regulate mesenchymal proliferation and differentiation. Here, we want to gain deeper insight into the molecular function of Wnt signaling in ureter development in the mouse by using a combination of tissue specific gene targeting studies in vivo, pharmacological activation and inhibition in explant cultures, and large scale molecular assays. Specifically, we wish to characterize the possible interaction of Wnt signaling with Shh and Bmp4 signaling in mesenchymal proliferation and differentiation, and identify and characterize Wnt-dependent transcription factor activities that mediate specific cellular programs in the ureteric mesenchyme. Here, one focus will be analysis of the T-box transcription factor genes Tbx2 and Tbx3. We expect from these studies new insights in the molecular mechanisms that control smooth muscle cell differentiation of visceral organs, and into the etiology of congenital obstructive nephropathy.

输尿管收缩活动的结构基础是平滑肌细胞和纤维弹性材料的外部间充质投资，其通过多步骤细胞程序从间充质前体细胞的未分化池产生。虽然输尿管壁的先天性异常是常见的，并可能对肾功能产生有害的后果，但对输尿管间充质发育的分子回路知之甚少。在第一个资助期，我们已经表明，来自输尿管上皮的Wnt信号通过经典的Ctnnb 1依赖性途径来调节间充质增殖和分化。在这里，我们希望通过结合体内组织特异性基因靶向研究、外植体培养物中的药理学激活和抑制以及大规模分子测定来更深入地了解Wnt信号传导在小鼠输尿管发育中的分子功能。具体而言，我们希望表征Wnt信号与Shh和Bmp 4信号在间充质增殖和分化中的可能相互作用，并鉴定和表征介导输尿管间充质中特定细胞程序的Wnt依赖性转录因子活性。这里，一个焦点将是分析T-box转录因子基因Tbx 2和Tbx 3。我们期望从这些研究中获得控制内脏器官平滑肌细胞分化的分子机制的新见解，以及先天性梗阻性肾病的病因学。