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: 8460149
• 负责人: HENK ROELINK
• 金额: $ 33.45万
• 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/8460149
• 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.

描述（由申请人提供）：Sonic Hedgehog （Shh）是一种信号分子，经过翻译后修饰，导致在蛋白质上添加两个亲脂性片段，使其与膜相关。尽管有这些修饰，在发育过程中，在干细胞壁龛中，在肿瘤中，Shh信号通常发送到离合成位点几个细胞直径远的细胞。两个相关的分子，Disp1和Ptc1，分别是Shh分泌和邻近细胞摄取所必需的。据推测，Shh的运输涉及Disp1和Ptc1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），从而介导远程运输，同时产生Shh活性梯度。三个中心观察结果支持这一假设，i/没有Disp1的细胞不分泌Shh， ii/周围细胞中的Ptch1是摄取Shh所必需的，iii/没有Disp1的组织运输Shh的能力较差。Ptch1和Disp1是一个质子驱动的三聚体反转运蛋白大家族的成员，第一个目的是测试Ptch1和Disp1的功能是否需要Shh的平面胞分裂。在目的2中，讨论了运输的尖基底极性以及响应，以调和基底外侧运输与初级纤毛的顶端定位。目的3和4探讨Shh的行程，以及Ptch1和Disp1的质子驱动泵活性在Shh运输中的作用，以及Smoothened的相关重新定位。