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）：形态剂是分子，在不同的浓度和信号传导阈值下指定不同的细胞命运。这些“产生”分子提供了在组织组装过程中产生模式的基本机制。生长因子的骨形态发生蛋白（BMP），WNT和刺猬家族的成员，该家族对于发育模式而言至关重要，并且参与了许多疾病过程，也表现为形态学。因此，深入了解组织如何组装和修复需要深入了解形态梯度建立和维持的分子机制。 尽管它已经确定硫酸乙酰肝素蛋白聚糖（HSPG）会影响形态剂指定的模式事件，但直到最近才得知HSPG控制形态学梯度本身本身。 Glypicans是一个综合膜蛋白聚糖的家族，已知会影响从人类到线虫的生长控制和模式。在机翼发育过程中，两种果蝇蛋白聚糖，dally和dally样（DLP）已被证明可以控制形态剂的处置，脱皮术（DPP），一个BMP4同源物和无翼（WG）。我们提出了DALLY和DLP控制形态梯度的详细生物物理和分子遗传分析。这些研究包括测量这些蛋白聚糖与形态受体和形态学受体的分子相互作用的平行实验，以及对它们对形态学分布的影响，发育翼的信号传导和周转的体内分析。 DALLY和DLP在影响DPP和WG分布的能力上显示出质和定量差异，我们希望了解这些差异的分子基础。总而言之，我们提出以下目标：目标1：使用各种提供动力学和亲和力数据的生物物理测量方法，确定Dally和DLP与形态和形态学受体的物理相互作用；目标2：比较Dally和DLP在影响体内形态学信号传导和分布以及这些活动的结构基础方面的差异活动； AIM 3：测量Dally和DLP对体内形态学运动和周转的影响。