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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：
7858541
负责人：
AMY A KIGER
金额：
$ 28.24万
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/7858541
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，部分是通过定义和控制膜室特性的特定磷脂磷酸酯(PIP)的局部调节来传达的。重要的是，磷脂酰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缺陷有关，尽管发育病理的细胞基础尚不清楚。肌管蛋白编码一种保守的磷脂酰肌醇3-磷酸磷酸酶，它是PI(3)P和PI(3，5)P2脂类的负调节因子，对内体和溶酶体具有已知的作用。后生动物中肌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，分别代表催化活性和非活性形式。肌管蛋白亚家族成员MTM1和MTMR2的人类突变分别与肌小管性肌病、神经病变和Charcot-Marie Tooth病的不孕症相关，这表明差异调节、肌醇磷脂底物池和/或其他中介因素的作用。果蝇基因组编码六个人类肌管蛋白家族中每一个家族的一个同源基因，这代表了一个理想的系统，可以通过发育遗传学分析来剖析不同的磷脂酰肌醇途径。我们鉴定了果蝇MTMR2和MTM1的肌管蛋白同源物是细胞形态发生所必需的，与肌管蛋白功能丧失相关的晚期内小体和细胞骨架调节缺陷。我们的具体目标是阐明依赖于果蝇细胞和动物的遗传操作，调节和响应肌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的动态分析，以表征肌管蛋白依赖的细胞过程，并确定细胞伸长所需的体内肌醇磷脂库。为了阐明肌管蛋白调控和反应所需的因素，我们将对肌管蛋白的形态表型进行全基因组RNAi筛选。最后，我们将确定肌管蛋白在果蝇发育中的定位动态和功能丧失要求。这项研究将提供对细胞空间调节和疾病重要的磷脂酰肌醇途径的见解。