Novel functions for NMDARs in neural crest development

NMDAR 在神经嵴发育中的新功能

• 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
• 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

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，可产生大量的神经细胞和非神经细胞