Novel functions for NMDARs in neural crest development

NMDAR 在神经嵴发育中的新功能

基本信息

批准号：
10645523
负责人：
HOWARD I SIROTKIN
金额：
$ 42.85万
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：
2023
资助国家：
美国
起止时间：
2023-09-06 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10645523
关键词：
Address Adhesions Afferent Neurons Autonomic nervous system Biological Assay Brain Calcium Cardiac Cardiac Myocytes Cartilage Cations Cells Chondrocytes Complex Cytoplasmic Tail Data Defect Development Disease Electrophysiology (science)Embryo Endowment Enteral Enteric Nervous System Epilepsy Event Exclusion Fertilization Foundations Functional disorder Glutamate Receptor Hour Immunohistochemistry Intellectual functioning disability Ion Channel Knowledge Larva Learning MK801 Measures Mediating Memory Monitor Motor Mutation N-Methyl-D-Aspartate Receptors NMDA receptor A1 Neural Crest Neural Crest Cell Neurodevelopmental Disorder Neuroepithelial Cells Neurons Pathogenesis Pathology Perception Peripheral Nervous System Permeability Phenotype Physiological Pigments Play Process Proliferating Property Proteins Receptor Signaling Reporter Reporter Genes Role Schwann Cells Signal Transduction Specific qualifier value Synapses Synaptic Transmission Tertiary Protein Structure Tissues Transgenic Organisms Work Zebrafish aspartate receptor autism spectrum disorder cell motility cell type clinical phenotype craniofacial experimental study melanocyte melanoma migration multipotent cell mutant nerve stem cell neural neuroregulation neurotransmission novel receptor receptor function scaffold stem stem cell proliferation synaptic function trafficking

项目摘要

The neural crest (NC)is a multipotent cell type that gives rise to a host of neural and non-neural tissues including the craniofacial cartilage, pigments cells and the peripheral nervous system. NC development is well-studied, and many factors regulating NC specification, proliferation and migration have been described. We unexpectedly discovered that mutants that lack the obligatory N-Methyl-D- Aspartate receptor (NMDAR) subunit (grin1 mutants) show excess craniofacial cartilage and melanocytes suggesting a previously unknown role for NMDARs in non-neural NC development. NMDARs are glutamate-gated cation channels that are critical synaptic proteins and play a key role in excitatory neurotransmission. Almost nothing is known about NMDAR function in NC and the grin1 mutants offer a unique opportunity to explore this connection. In our first aim, we will determine whether NMDARs broadly modulate NC proliferation, migration or act in a subset of NC lineages. We will then assess the mechanisms of NMDAR NC function in the second aim. Here, we will ask whether NDMARs modulate of Ca2+ influx in NC and if NMDAR activity is required in NC or another cell type. Lastly, we will determine which NMDAR subunits mediate the effect on NC as the composition of NMDARs is critical to its properties as an ion channel and modulate numerous protein interactions. Our work demonstrates a novel role for NMDARs in regulation of NC development and our proposed studies lay the foundation for understanding the mechanisms at play. NMDAR dysfunction is associated with several neurodevelopmental disorders include autism, epilepsy and intellectually disability. Elucidating the activity of NMDAR in NC has implications for both unraveling underappreciated NC related phenotypes in these disorders and for delineating NMDAR functions that may be relevant to neurocristopathies.

神经嵴 (NC) 是一种多能细胞类型，可产生大量神经和非神经细胞组织包括颅面软骨、色素细胞和周围神经系统。数控 NC 的发展已得到充分研究，许多因素调节 NC 规范、增殖和迁移已被描述。我们意外地发现缺乏必需的 N-甲基-D- 的突变体天冬氨酸受体 (NMDAR) 亚基（grin1 突变体）显示颅面软骨和黑色素细胞过多表明 NMDAR 在非神经 NC 发展中具有先前未知的作用。 NMDAR 是谷氨酸门控阳离子通道是关键的突触蛋白，在兴奋性中发挥关键作用神经传递。关于 NMDAR 在 NC 中的功能几乎一无所知，而 grin1 突变体提供了探索这种联系的独特机会。在我们的第一个目标中，我们将确定 NMDAR 是否广泛调节 NC 增殖、迁移或在 NC 谱系的子集中发挥作用。然后我们将评估 NMDAR NC 在第二个目标中发挥作用的机制。在这里，我们将询问 NDMAR 是否调节 NC 中的 Ca2+ 流入以及 NC 或其他细胞类型是否需要 NMDAR 活性。最后，我们将确定哪些 NMDAR 亚基介导对 NC 的影响，因为 NMDAR 的组成至关重要其作为离子通道的特性并调节许多蛋白质相互作用。我们的工作展示了 NMDAR 在 NC 发展调节中的新作用和我们提出的研究奠定了基础了解发挥作用的机制。 NMDAR 功能障碍与多种因素有关神经发育障碍包括自闭症、癫痫和智力障碍。阐明 NMDAR 在 NC 中的活性对于揭示未被充分认识的 NC 相关表型具有重要意义在这些疾病中以及描绘可能与神经嵴病相关的 NMDAR 功能。