Shaping a Shh morphogen gradient

塑造 Shh 形态发生素梯度

• 批准号: 7142893
• 负责人: MICHAEL KANE COOPER
• 金额: $ 16.51万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142893
• 关键词: Mammalia; adduct; diffusion; lipids; proteins; role; tissues

DESCRIPTION (provided by applicant): Members of the Hedgehog (Hh) family of signaling proteins play critical roles in coordinating cell growth and differentiation. Many embryonic tissues and structures require Hh signaling for their formation during development and thus a large number of birth defects have been associated with reduced Shh signaling. One of the more striking malformations is holoprosencephaly that may result from reduced Sonic hedgehog (Shh) signaling by a variety of means including genetic mutations in Shh and other pathway components, teratogen exposure, or inborn errors of cholesterol biosynthesis. Hh proteins are secreted from a localized source and elicit distinct, concentration-dependent responses in a field of neighboring cells. A unique feature of Hh protein biogenesis is the production of a mature signaling domain that is covalently modified by cholesteryl and palmitoyl adducts. Given the importance of morphogen distribution, we are interested in the detailed roles of the lipid modifications on the spatial deployment of Shh in the developing neural tube. Towards this end, we have developed a visualizable Shh molecule to characterize the cellular mechanisms that package, propagate and receive a morphogen with unique biochemical properties. We also propose to generate lines of transgenic zebrafish with localized expression of photoactivatible Shh-GFP to measure the contribution of each adduct on the rate of Shh diffusion and degradation.

描述（由申请人提供）：Hedgehog（Hh）信号蛋白家族成员在协调细胞生长和分化中发挥关键作用。许多胚胎组织和结构在发育过程中需要Hh信号传导来形成，因此大量的出生缺陷与Shh信号传导减少有关。其中一种更引人注目的畸形是前脑无裂畸形，其可能是由于通过多种方式减少Sonic hedgehog（Shh）信号传导导致的，包括Shh和其他通路组分的基因突变、致畸剂暴露或胆固醇生物合成的先天性错误。Hh蛋白从局部来源分泌，并在邻近细胞的区域中引起不同的浓度依赖性反应。Hh蛋白生物合成的一个独特特征是产生一个成熟的信号传导结构域，该结构域被胆固醇和棕榈酰加合物共价修饰。由于形态发生分布的重要性，我们感兴趣的是详细的作用，脂质修饰的空间部署的Shh在发展中的神经管。为此，我们开发了一种可视化的Shh分子来表征包装，繁殖和接收具有独特生化特性的形态发生素的细胞机制。我们还建议产生线的转基因斑马鱼与本地化表达的光活化的Shh-GFP测量的贡献，每个加合物的速率上的Shh扩散和降解。