Novel functions for NMDARs in neural crest development

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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.