The roles of Ptch1 and Disp1 in the formation of the Shh gradient

Ptch1和Disp1在Shh梯度形成中的作用

• 批准号: 8082848
• 负责人: HENK ROELINK
• 金额: $ 29.17万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-18 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8082848
• 关键词: Address; Agreement; Apical; Caliber; Cells; Cilia; Complex; Data; Development; Diffusion; Embryonic Development; Endocytosis; Epithelium; Erinaceidae; Event; Family; Lateral; Lipoproteins; Location; Malignant Neoplasms; Mediating; Membrane; Modeling; Modification; Molecular; Mutation; Pathway interactions; Post-Translational Protein Processing; Proteins; Protons; Pump; Resistance; Role; Series; Side; Signal Transduction; Signaling Molecule; Site; Source; Testing; Tissues; Vesicle; antiporter; base; extracellular; human SMO protein; in vivo; late endosome; member; morphogens; mutant; neural plate; notochord; particle; polarized cell; research study; response; segregation; smoothened signaling pathway; stem cell niche; trafficking; transcytosis; tumor; uptake

DESCRIPTION (provided by applicant): Sonic Hedgehog (Shh) is a signaling molecule that undergoes post-translational modifications resulting in the addition two lipophilic moieties to the protein, rendering it obligatory membrane associated. Despite these modifications, during development, in stem cell niches, and in tumors Shh signals to cells often several cell diameters away from the sites of synthesis. Two related molecules, Disp1 and Ptc1, are required for the secretion of Shh and its uptake in neighboring cells respectively. It is hypothesized that transport of Shh involves the reiterated and complementary actions of Disp1 and Ptc1 generating and absorbing Shh containing complexes (either lipoprotein particles or exosomes) thus mediating long-range transport while generating a Shh activity gradient. Three central observations support this hypothesis, i/ cells without Disp1 do not secrete Shh, ii/ Ptch1 in surrounding cells is required for the uptake of Shh and iii/ tissues without Disp1 are less able to transport Shh. Ptch1 and Disp1 are members of a large family of trimeric, proton driven antiporters, and in the first aim it is tested if Ptch1 and Disp1 function is required for planar transcytosis of Shh. In aim 2 the apicobasal polarity of the transport as well as the response is addressed, to reconcile basolateral transport with the apical localization of the primary cilium. Aims 3 and 4 address the Shh itinerary as well as the role of the putative proton driven pump activity of Ptch1 and Disp1 in the transport of Shh, and the associated relocation of Smoothened. PUBLIC HEALTH RELEVANCE: Cell to cell signaling mediated by Sonic Hedgehog (Shh) is critically important for normal embryonic development and correct function of many stem cell niches. Furthermore, inappropriate expression of Shh is a determining step in the formation of many common cancers. We propose a series of experiments that address the molecular mechanism by which Shh is secreted and transported to neighboring cells.

描述（由申请人提供）：Sonic Hedgehog（Shh）是一种信号分子，其经过翻译后修饰，导致向蛋白质中添加两个亲脂性部分，使其与膜结合。尽管有这些修饰，在发育过程中，在干细胞龛和肿瘤中，Shh向细胞发出信号，通常距离合成位点几个细胞直径。两个相关的分子，Disp 1和Ptc 1，分别需要分泌Shh和其在邻近细胞中的摄取。假设Shh的转运涉及Disp 1和Ptc 1的重复和互补作用，产生和吸收含有Shh的复合物（脂蛋白颗粒或外泌体），从而介导长程转运，同时产生Shh活性梯度。三个中心的观察结果支持这一假设，i/没有Disp 1的细胞不分泌Shh，ii/周围细胞中的Ptch 1是摄取Shh所必需的，iii/没有Disp 1的组织不太能够运输Shh。Ptch 1和Disp 1是三聚体质子驱动的反向转运蛋白大家族的成员，并且在第一个目的中，测试Ptch 1和Disp 1功能是否是Shh的平面转胞吞所需的。在目标2的apicobasal极性的运输，以及解决的反应，调和基底侧运输与顶端本地化的初级纤毛。目的3和4地址的Shh行程，以及假定的质子驱动泵活动的Ptch 1和Disp 1在运输的Shh的作用，和相关的搬迁的平滑。 公共卫生相关性：由Sonic Hedgehog（Shh）介导的细胞间信号传导对于正常胚胎发育和许多干细胞龛的正确功能至关重要。此外，Shh的不适当表达是许多常见癌症形成的决定性步骤。我们提出了一系列的实验，解决的分子机制，嘘分泌和运输到邻近细胞。