Molecular Mechanisms of Morphogen Gradient Formation

形态发生梯度形成的分子机制

• 批准号: 7086228
• 负责人: Hiroshi Nakato
• 金额: $ 27.74万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086228
• 关键词: Drosophilidae; biological signal transduction; biosensor device; cell communication molecule; cell surface receptors; chimeric proteins; electrophoresis; gene mutation; genetic regulation; heparan sulfate; histogenesis; intermolecular interaction; protein biosynthesis; protein localization; protein structure function; protein transport; proteoglycan; receptor binding

DESCRIPTION (provided by applicant): Morphogens are molecules that specify different cell fates at distinct concentration and signaling thresholds. These "form generating" molecules provide a fundamental mechanism of generating pattern during tissue assembly. Members of the bone morphogenetic protein (BMP), Wnt, and Hedgehog families of growth factors, long known to be essential for developmental patterning and involved in many disease processes, also behave as morphogens. An in depth understanding of how tissues are assembled and repaired, therefore, requires insight into the molecular mechanism of morphogen gradient establishment and maintenance. While it has established that heparan sulfate proteoglycans (HSPGs) affect patterning events specified by morphogens, only recently has it been appreciated that HSPGs control morphogen gradients per se. Glypicans are a family of integral membrane proteoglycans known to affect growth control and patterning from humans to nematodes. Two Drosophila proteoglycans, Dally and Dally-like (Dlp), have been shown to control the disposition of the morphogens, Decapentaplegic (Dpp), a BMP4 homolog, and Wingless (Wg), during wing development. We propose a detailed biophysical and molecular genetic analysis of how Dally and Dlp control morphogen gradients. These studies include parallel experiments measuring the molecular interactions of these proteoglycans with morphogens and morphogen receptors, along with in vivo analysis of their effects on morphogen distributions, signaling and turnover in the developing wing. Dally and Dlp show qualitative and quantitative differences in their capacity to affect Dpp and Wg distribution and we wish to understand the molecular basis of these differences. In sum, we propose the following objectives: Aim 1: Determine the physical interaction of Dally and Dlp with morphogens and morphogen receptors using a variety of biophysical measures that provide kinetic and affinity data; Aim 2: Compare the differential activities of Dally and Dlp in affecting morphogen signaling and distribution in vivo and the structural basis of those activities; Aim 3: Measure the effects of Dally and Dlp on morphogen movement and turnover in vivo.

描述（由申请人提供）：形态发生素是在不同浓度和信号阈值下指定不同细胞命运的分子。这些“形式生成”分子提供了组织组装过程中生成图案的基本机制。骨形态发生蛋白 (BMP)、Wnt 和 Hedgehog 生长因子家族的成员长期以来被认为对发育模式至关重要并参与许多疾病过程，它们也具有形态发生素的作用。因此，深入了解组织如何组装和修复，需要深入了解形态发生素梯度建立和维持的分子机制。 虽然已经确定硫酸乙酰肝素蛋白聚糖 (HSPG) 会影响形态发生素指定的图案形成事件，但直到最近才认识到 HSPG 本身控制形态发生素梯度。磷脂酰肌醇蛋白聚糖是一个完整膜蛋白聚糖家族，已知会影响从人类到线虫的生长控制和模式。两种果蝇蛋白聚糖，Dally 和 Dally-like (Dlp)，已被证明可以在翅膀发育过程中控制形态发生素 Decapentaplegic (Dpp)（BMP4 同源物）和 Wingless (Wg) 的处置。我们提出了关于 Dally 和 Dlp 如何控制形态发生素梯度的详细生物物理和分子遗传学分析。这些研究包括测量这些蛋白聚糖与形态发生素和形态发生素受体的分子相互作用的平行实验，以及它们对发育中翅膀中形态发生素分布、信号传导和周转的影响的体内分析。 Dally 和 Dlp 在影响 Dpp 和 Wg 分布的能力方面表现出定性和定量差异，我们希望了解这些差异的分子基础。总之，我们提出以下目标： 目标 1：使用提供动力学和亲和力数据的各种生物物理措施确定 Dally 和 Dlp 与形态发生素和形态发生素受体的物理相互作用；目标2：比较Dally和Dlp在体内影响形态原信号传导和分布的差异活性以及这些活性的结构基础；目标 3：测量 Dally 和 Dlp 对体内形态原运动和周转的影响。