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

• 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
• 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

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.

诱导过程和枝晶顶端极化的分子机制 在胚胎神经元发育期间 哺乳动物胚胎脑发育的早期和基本事件是神经元极化，其中不同的极化是不同的。 形成轴突和树突隔室。轴突和树突在分子组成上固有地不同 它们的细胞质、细胞骨架和质膜。这些差异构成了独特形态的基础， 这些隔室的功能，并负责大脑中的定向信息流。神经元畸变 两极分化导致发育神经病理学、智力残疾、癫痫、自闭症谱系障碍， 神经精神病理学有丝分裂后新皮层和海马CA1区双极极性的建立 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 从双极神经元的前导过程发展而来，而拖尾过程将成为轴突。 轴突的特化已经主导了对神经元极化的研究，产生了对神经元极化的理解。 轴突身份，其规格和生长的机制。还作出了很大努力， 阐明了控制枝晶形态发生后期事件的机制--生长、分支和结构 可塑性然而，导致双极极性的事件和随后的顶端树突的发育， 仍然难以捉摸我们提出，通过局部组装产生的明显更高的环GMP（cGMP）， cGMP生产机制在发展中的锥体神经元的前沿，促进双极极性， 引导突起形成和顶端树突发育。使用最先进的寿命衰减FLIM-FRET 急性切片中小鼠发育中锥体神经元的cGMP测量，结合尖端遗传学 操作，以及cGMP生产的局部化，定向光遗传学操作，本研究旨在 确定cGMP在极性建立和顶端树突发育期间的时空调节， 并确定其在体内锥体神经元发育中的机制基础。我们的研究将提供重要的 轴突和顶端树突发生的早期分子事件的理解进展 建立在啮齿动物大脑中的主要兴奋性神经元，并将有助于识别 由异常发育引起的发育性神经病理学的分子靶点和治疗剂的开发 轴突和树突发育。