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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.

启动引导过程和顶端树突极化的分子机制胚胎神经元发育过程中哺乳动物胚胎大脑发育的一个早期且重要的事件是神经元极化，其中不同的形成轴突和树突室。轴突和树突的分子组成本质上不同它们的细胞质、细胞骨架和质膜。这些差异构成了独特的形态和这些区室的功能，并负责大脑中定向信息流。神经元畸变极化会导致发育性神经病理学、智力障碍、癫痫、自闭症谱系障碍和神经精神病理学。有丝分裂后新皮质和海马 CA1 的双极极性建立锥体神经元祖细胞标志着轴突和顶端树突的极化。顶端树突将从双极神经元的前导过程发展而来，而尾随过程将成为轴突。轴突的规格主导了神经元极化的研究，使人们了解了轴突身份、其规范和生长的潜在机制。也付出了很多努力阐明控制树突形态发生后期事件的机制——生长、分支和结构可塑性。然而，导致双极极性和随后顶端树突发育的事件，仍然难以捉摸。我们建议通过局部组装产生明显更高的循环 GMP (cGMP) cGMP 生产机制位于锥体神经元发育的前沿，促进双极极性，主导过程的形成和顶端树突的发育。使用最先进的寿命衰减 FLIM-FRET 小鼠急性切片中发育锥体神经元的 cGMP 测量，结合尖端遗传 cGMP 生产的操作和局部定向光遗传学操作，本研究旨在确定极性建立和顶端树突发育过程中 cGMP 的时空调节，并确定其在体内发育锥体神经元的机制基础。我们的研究将提供重要的对轴突和顶端树突期间发生的早期分子事件的理解取得了进展在啮齿动物大脑的主要兴奋性神经元中建立，并将有助于识别异常引起的发育性神经病理学的分子靶点和治疗方法的开发轴突和树突发育。