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Planar cell polarity control of axon guidance

轴突引导的平面细胞极性控制

基本信息

批准号：
10737486
负责人：
Cecilia B Moens
金额：
$ 61.62万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737486
关键词：
3-Dimensional Actins Animals Anterior Axon Behavior Brain CRISPR screen Cell Transplantation Cell surface Cells Complex Cues Cytoskeleton Decision Making Dorsal Embryo Environment Epithelium Fascicle Floor Genes Genetic Genetic Markers Genetic study Goals Growth Growth Cones Image In Vitro Individual Interneurons Invertebrates Ipsilateral Learning Left Locomotion Mediating Membrane Molecular Motor Nervous System Neuroepithelial Neurons Outcome Pathway interactions Play Posture Process Proteins Reagent Resolution Role Sensory Signal Pathway Signal Transduction Specific qualifier value Spinal Spinal Cord Structure System Testing Time Vertebral column Visualization Visualization software Work Zebrafish axon growth axon guidance cell motility gene function in vivo in vivo Model migration molecular asymmetry mutant neural circuit neurodevelopment neuron development neuronal growth optogenetics planar cell polarity receptor response transmission process

项目摘要

PROJECT SUMMARY Midline crossing by dorsal commissural axons is a prominent feature of vertebrate and invertebrate nervous systems, necessary for the left-right coordination of sensory and motor systems, locomotion, and posture. In the vertebrate spinal cord, dorsal commissural axons extend towards and cross the midline floorplate, and then turn longitudinally to ascend towards the brain. While the growth cone’s voyage to and across the floorplate has been intensively studied, its final decision—whether to ascend or descend after emerging from the midline—is less well understood. Genetic studies clearly implicate the Planar Cell Polarity (PCP) pathway in this decision, but our understanding of how PCP signaling guides the growth cone is incomplete. The PCP pathway is a cell-cell contact-mediated signaling pathway that transmits polarity information between cells to orient them for directed migration. Yet our mechanistic understanding of the role of PCP signaling in commissural axon guidance is largely informed by studies of isolated growth cones in vitro. Thus, A major gap in our understanding of commissural axon guidance is the role that cell contact-mediated cues play in longitudinal guidance. Using the transparent zebrafish embryo to visualize the axons and growth cones of single identified pioneer commissural interneurons in PCP mutants, we have found that core components of the PCP signaling pathway are required equally within the commissural neuron and in its environment for correct axon targeting. PCP proteins localize to the growth cone and to the cells on its trajectory. We hypothesize that the growth cone uses PCP signaling to polarize its growth in response to planar-polarized cues in its immediate neuroepithelial environment. In Aim 1 we will test this hypothesis by locating, in space and time, the requirement for PCP core components in the growth cone environment, and by quantitative live imaging of growth cone membrane and actin dynamics as it is making its anterior targeting decision. In Aim 2 we will expand our scope to discover the commissural axon guidance role of proteins that have been implicated in PCP signaling elsewhere through a targeted G0 CRISPR screen. Finally, in Aim 3 we will expand our scope once again to test the hypothesis that PCP signaling functions broadly in longitudinal axon guidance in the spinal cord. The successful outcome of this work will be a deep mechanistic understanding of how the dorsal commissural neuron growth cone is polarized for anterior growth in vivo by the Planar Cell Polarity pathway, to enable it to build sensory circuits controlling locomotion and posture.

项目总结