Mechanisms of membrane ratcheting during cell intercalation

细胞嵌入过程中膜棘轮机制

基本信息

批准号：
9440874
负责人：
James Todd Blankenship
金额：
$ 43.99万
依托单位：
UNIVERSITY OF DENVER (COLORADO SEMINARY)
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-11 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9440874
关键词：
AGFG1 gene Actomyosin Adhesions Architecture Automobile Driving Behavior Biochemical C-terminal Carcinoma Cell Adhesion Cell Polarity Cell Shape Cell membrane Cell surface Cells Clathrin Cochlea Complex Contracts Coupled Cues Cytoplasm Data Development Developmental Process Disease Drosophila genus Embryo Embryonic Development Endocytosis Epithelial Epithelial Cells Epithelium Event Generations Goals Growth Guanosine Triphosphate Homeostasis Human Individual Intention Intercalated Cell Kidney Length Link Lipids Measures Membrane Monomeric GTP-Binding Proteins Morphogenesis Movement Myosin Type II Nature Neoplasm Metastasis Organ PH Domain Palate Pathway interactions Pattern Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphotransferases Physiologic pulse Process Proteins Recruitment Activity Recycling Resolution Role Shapes Signal Transduction Skin Tissues Work cell age experimental analysis gastrulation genetic approach genetic manipulation insight intercalation live cell imaging loss of function repaired response small molecule trafficking

项目摘要

Mechanisms of membrane ratcheting during cell intercalation The ability of cells in epithelial sheets to under neighbor cell rearrangements is essential to tissue shaping as well as repair and homeostasis mechanisms. In the Drosophila embryonic epithelium, individual cells are able to either consolidate cell-cell contacts or direct neighbor exchange movements through the contraction of vertical T1 interfaces and the subsequent resolution of horizontal T3 interfaces. A recent appreciation has been that changes in these topological relationships occur in response to pulses of actomyosin activity; however, the mechanism by which cell shape changes are maintained after contractile periods has been unclear. Here, we explore the function of a membrane-dependent cell shape ratcheting mechanism. We examine how the ratcheting mechanism is initiated by small GTPase GEF activity, and how this activity can be linked to plasma membrane dynamics. We will determine the function of PtdIns lipids in GEF recruitment and early morphogenesis, and identify the PtdIns phospho-species and PtdIns kinases that localize membrane ratcheting. We will further identify the relative roles of actomyosin networks and endocytic pathways in the termination and consolidation of ratcheting events, and the degree of coordination between these processes. Finally, the membrane trafficking pathways that are active in epithelial cells during gastrulation movements will be examined, and the function of recycling and endosomal pathways in driving interface contraction and growth will be determined. The proposed work will be a highly interdisciplinary project driven by a combination of quantitative analysis of experimental live-cell imaging data with physical and genetic manipulation of these processes. The results are expected to yield a comprehensive mechanistic insight into how cytoskeletal force generation is coupled with targeted remodeling of the plasma membrane to drive changes in cell shapes and topologies.

细胞插入过程中膜棘轮的机理上皮板中细胞在邻居细胞重排下的能力是必不可少的进行组织形状以及修复和稳态机制。在果蝇中胚胎上皮，单个细胞能够巩固细胞 - 细胞接触或直接通过垂直T1界面收缩的邻居交换运动以及随后的水平T3接口的分辨率。最近的赞赏这些拓扑关系的变化是响应于肌球蛋白活性；但是，细胞形状变化的机制是尚不清楚收缩期之后维护。在这里，我们探索了膜依赖性细胞形状棘轮机制。我们检查了棘轮机制是由小的GTPase GEF活性启动的，以及该活动如何链接到质膜动力学。我们将确定GEF中ptdins脂质的功能募集和早期形态发生，并识别Ptdins磷酸物种和定位膜棘轮的PTDINS激酶。我们将进一步确定亲戚肌动球蛋白网络和内吞途径在终止中的作用棘轮事件的合并以及这些之间的协调程度过程。最后，在上皮细胞中活跃的膜运输途径将检查胃移动期间，以及回收的功能将确定驱动界面收缩和生长的内体途径。这拟议的工作将是一个高度跨学科的项目，由具有物理和遗传的实验活细胞成像数据的定量分析操纵这些过程。结果预计将产生全面的关于细胞骨架力的产生方式与靶向的机械洞察力质膜的重塑以驱动细胞形状和拓扑的变化。