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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：
7993617
负责人：
AMY A KIGER
金额：
$ 9.99万
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：
2010
资助国家：
美国
起止时间：
2010-01-08 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7993617
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 Homeostasis Homologous Gene Human Lipids Lysosomes Malignant Neoplasms Mediating Membrane Molecular Morphogenesis Morphology Mutation Neuropathy Pathology Pathway interactions Phenotype Phosphatidylinositols Phosphoinositide Pathway Phosphoric Monoester Hydrolases Protein Family Proteins RNA Interference Regulation Research Research Personnel Role Series Signal Transduction Sterility System Testing Yeasts base design developmental genetics functional genomics genetic analysis genetic manipulation genome-wide high throughput screening in vivo inorganic phosphate insight late endosome loss of function mutant myotubularin novel phosphatidylinositol 3-phosphate phosphoinositide 3-phosphate programs protein expression 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）：细胞形状是动态空间调节的结果，部分是通过特定磷酸肌醇磷酸酯（PIPs）的局部调节来传达的，PIPs定义和控制膜室特性。重要的是，尽管发育病理的细胞基础尚不清楚，但磷酸肌苷调节因子的突变与导致人类退行性疾病和癌症的形态缺陷有关。肌管蛋白编码一种保守的磷酸肌苷3-磷酸磷酸酶，是PI(3)P和PI(3,5)P2脂质的负调节因子，已知在核内体和溶酶体中起作用。在后生动物中肌小管蛋白功能的一个令人困惑的方面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。肌小管蛋白亚家族成员MTM1和MTMR2的人类突变分别与肌小管肌病、神经病变和沙克-玛丽氏病的不育有关，提示差异调节、磷酸肌肽底物池和/或其他介导因素的作用。果蝇基因组为6个人类肌管蛋白家族中的每一个家族编码一个同源物，代表了一个理想的系统，通过发育-遗传分析来解剖不同的磷酸肌肽途径。我们发现果蝇的肌管蛋白同源物与人类的MTMR2和MTM1是细胞形态发生所必需的，其后期内体和细胞骨架调节的缺陷与肌管蛋白功能丧失有关。我们的具体目标是通过果蝇细胞和动物的遗传操作，阐明调节和响应肌小管蛋白依赖的细胞形态发生功能的途径。我们将进行基于细胞动力学的分析，以表征肌小管蛋白依赖的细胞过程，并确定细胞延伸所需的体内磷酸肌肽池。为了阐明肌小管蛋白调控和反应所需的因素，我们将对肌小管蛋白形态表型进行全基因组RNAi筛选。最后，我们将确定果蝇发育过程中肌小管蛋白的定位动力学和功能丧失需求。这项研究将提供对细胞空间调节和疾病重要的磷酸肌苷途径的见解。