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）：刺猬（HH）信号蛋白家族的成员在协调细胞生长和分化方面起关键作用。许多胚胎组织和结构都需要HH信号传导才能在发育过程中形成，因此大量的先天缺陷与SHH信号的降低有关。最引人注目的畸形之一是尸体脑畸形，可能是由于Sonic刺猬（SHH）信号通过多种手段降低而导致的，包括SHH和其他途径成分的遗传突变，Teratogen暴露或胆固醇生物合成的胆固醇误差。 HH蛋白从局部来源分泌，并在相邻细胞领域引起独特的浓度依赖性反应。 HH蛋白生物发生的一个独特特征是生产成熟的信号域，该信号域是由胆固醇和棕榈酰加合物共价修饰的。鉴于形态学分布的重要性，我们对脂质修饰在发育中的神经管中SHH的空间部署的详细作用感兴趣。为此，我们开发了一种可视化的SHH分子，以表征包装，传播和接收具有独特生化特性的形态学的细胞机制。我们还建议生成具有光活化SHH-GFP的局部表达的转基因斑马鱼的线，以测量每个加合物对SHH扩散和降解速率的贡献。