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Molecular Mechanisms that Initiate Apical Dendrite Development During Embryonic Neuronal Development

胚胎神经元发育过程中启动顶端树突发育的分子机制

基本信息

批准号：
10428460
负责人：
Maya Shelly
金额：
$ 39.2万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10428460
关键词：
Acute Affect Apical Architecture Axon Binding Bipolar Neuron Brain Cell membrane Complex Cues Cyclic GMP Cytoplasm Cytoskeleton Data Dendrites Development Developmental Therapeutics Program Electroporation Embryo Enzymes Epilepsy Event Fluorescence Resonance Energy Transfer Growth Hippocampus (Brain)Image Intellectual functioning disability Kinesin Lead Light Link Measurement Measures Mediating Methodology Mitosis Molecular Molecular Target Morphogenesis Morphology Motor Multipolar Neuron Mus Neurites Neuroepithelial Neurons Pathology Prevention Process Production Regulation Research Rodent Role Scaffolding Protein Second Messenger Systems Semaphorin-3A Signal Transduction Slice Specific qualifier value Work autism spectrum disorder base design disability excitatory neuron extracellular genetic approach genetic manipulation hippocampal pyramidal neuron in utero in vivo neocortical nerve stem cell neuron development neuropathology neuropsychiatric disorder neuropsychiatry optogenetics postnatal prevent progenitor receptor scaffold sensor spatiotemporal therapeutic development

项目摘要

Molecular mechanisms that initiate leading process and apical dendrite polarization during embryonic neuronal development An early and essential event in mammalian embryonic brain development is neuronal polarization, in which distinct axonal and dendritic compartments are formed. Axons and dendrites inherently differ in the molecular composition of their cytoplasm, cytoskeleton, and plasma membrane. These differences underlie the unique morphology and function of these compartments, and are responsible for directed information flow in the brain. Aberrations in neuron polarization lead to developmental neuropathologies, intellectual disability, epilepsy, autism spectrum disorders, and neuropsychiatric pathologies. Bipolar polarity establishment in postmitotic neocortical and hippocampal CA1 pyramidal neuron progenitors marks polarization of the axon and the apical dendrite. The apical dendrite will develop from the leading process of the bipolar neuron whereas the trailing process will become the axon. Specification of the axon has dominated studies on neuron polarization, yielding an understanding of the mechanisms underlying axonal identity, its specification and growth. Much effort has also been directed towards elucidation of the mechanisms that control later events in dendrite morphogenesis - growth, branching, and structural plasticity. However, the events leading to bipolar polarity and the subsequent development of the apical dendrite, have remained elusive. We propose that distinctly higher cyclic GMP (cGMP) generated via localized assembly of a cGMP production machinery at the leading edge of developing pyramidal neurons, promotes bipolar polarity, leading process formation, and apical dendrite development. Using state of the art lifetime decay FLIM-FRET cGMP measurements in mouse developing pyramidal neurons in acute slice, combined with cutting edge genetic manipulations, and localized, directed optogenetic manipulations of cGMP production, this study is designed to determine the spatio-temporal regulation of cGMP during polarity establishment and apical dendrite development, and to identify its mechanistic basis in developing pyramidal neurons in vivo. Our studies will provide important advance in the understanding of the early molecular events that take place during axon and apical dendrite establishment in principal excitatory neurons in the rodent brain, and will contribute to the identification of molecular targets and development of therapeutics for developmental neuropathologies resulting from abnormal axon and dendrite development.

启动先导过程和顶端枝晶极化的分子机制