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Function of Myotubularin Phosphoinositide Phosphatase in Morphogenesis

肌管蛋白磷酸肌醇磷酸酶在形态发生中的功能

基本信息

批准号：
7316824
负责人：
AMY A KIGER
金额：
$ 28.61万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7316824
关键词：
Animals Biological Assay Cell Cycle Kinetics Cell Shape Cell physiology Cells Cellular Morphology Centronuclear myopathy Charcot-Marie-Tooth Disease Cytoskeleton Data Defect Degenerative Disorder Development Disease Dissection Drosophila genome Drosophila genus Ecdysone Endosomes Family Family member Genetic Genome Homeostasis Homologous Gene Human Lipids Localized Lysosomes Malignant Neoplasms Mediating Membrane Molecular Morphogenesis Morphology Mutation Neuropathy Pathology Pathway interactions Phenotype Phosphatidylinositols Phosphoinositide Pathway Phosphoric Monoester Hydrolases Protein Family RNA Interference Regulation Research Research Personnel Role Series Signal Transduction Sterility System Testing Yeasts base design developmental genetics functional genomics genetic analysis genetic manipulation high throughput screening in vivo inorganic phosphate insight intracellular protein transport late endosome loss of function mutant myotubularin novel phosphatidylinositol 3-phosphate phosphoinositide 3-phosphate programs protein localization location response

项目摘要

DESCRIPTION (provided by applicant): Cell shape results from dynamic spatial regulation, in part conveyed through localized regulation of specific phosphoinositide phosphates (PIPs) that define and control membrane compartment identities. Importantly, mutations in phosphoinositide regulators are associated with morphology defects that contribute to human degenerative diseases and cancers, although the cellular bases of the developmental pathologies are not understood. Myotubularin encodes a conserved phosphoinositide 3-phosphate phosphatase, a negative regulator of PI(3)P and PI(3,5)P2 lipids with known roles on endosomes and lysosomes. A confounding aspect of myotubularin function in metazoans is the existence of six divergent protein families, representing both catalytically active and inactive forms. Human mutations in myotubularin sub-family members MTM1 and MTMR2 are associated with myotubular myopathy and neuropathy and sterility of Charcot-Marie Tooth disease, respectively, suggesting differential regulation, pools of phosphoinositide substrates and/or roles for other mediating factors. The Drosophila genome encodes for one homolog for each of the six human myotubularin families, representing an ideal system for the dissection of distinct phosphoinositide pathways through developmental-genetic analyses. We identified the Drosophila myotubularin homolog of human MTMR2 and MTM1 as necessary for cellular morphogenesis, with defects in late endosomes and cytoskeletal regulation associated with myotubularin loss of function. Our Specific Aims are designed to elucidate pathways that regulate and respond to myotubularin-dependent functions for cellular morphogenesis, relying on genetic manipulations in Drosophila cells and animals. We will perform kinetic cell-based assays to characterize the myotubularin-dependent cellular processes and to identify the in vivo phosphoinositide pools required for cellular elongation. To elucidate factors required for myotubularin regulation and responses, we will conduct genome-wide RNAi screens of myotubularin morphology phenotypes. Finally, we will determine the myotubularin protein localization dynamics and loss-of-function requirements in Drosophila development. This research will provide insights on phosphoinositide pathways important for cell spatial regulation and disease.

描述（由申请人提供）：细胞形状由动态空间调节引起，部分通过特定磷酸肌醇磷酸（PIP）的局部调节来传递，所述特定磷酸肌醇磷酸（PIP）限定和控制膜隔室身份。重要的是，磷酸肌醇调节因子的突变与导致人类退行性疾病和癌症的形态学缺陷相关，尽管发育病理学的细胞基础尚不清楚。肌管蛋白编码保守的磷酸肌醇3-磷酸磷酸酶，其是PI（3）P和PI（3，5）P2脂质的负调节剂，在核内体和溶酶体上具有已知的作用。一个令人困惑的方面，在后生动物中的肌管蛋白功能是存在六个不同的蛋白质家族，代表催化活性和非活性形式。人类突变的肌管蛋白亚家族成员MTM 1和MTMR 2分别与肌管肌病和神经病变和腓骨肌萎缩症的不育症，表明差异调节，池的磷酸肌醇底物和/或其他介导因子的作用。果蝇基因组编码一个同源物的六个人类myotubularin家族，代表了一个理想的系统，通过发育遗传分析的解剖不同的磷酸肌醇途径。我们确定了果蝇myotubularin同源物的人MTMR 2和MTM 1的细胞形态发生所必需的，在后期内体和细胞骨架调节与myotubularin功能丧失的缺陷。我们的特定目标旨在阐明依赖于果蝇细胞和动物中的遗传操作来调节和响应细胞形态发生的肌微管蛋白依赖性功能的途径。我们将进行动力学细胞为基础的测定，以表征肌微管蛋白依赖的细胞过程，并确定在体内细胞伸长所需的磷酸肌醇池。为了阐明肌管蛋白调节和反应所需的因素，我们将进行全基因组的肌管蛋白形态表型的RNAi筛选。最后，我们将确定myotubularin蛋白定位动力学和功能丧失的要求在果蝇的发展。这项研究将提供对细胞空间调节和疾病重要的磷酸肌醇途径的见解。