Molecular mechanisms that regulate p38 MAPK-dependent neuronal gene expression

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Project Summary. The nervous system comprises an extraordinary variety of neuronal cell types. A differentiated neuron type is defined by a unique gene expression pattern that determines its morphology, connectivity, and function. Deciphering developmental mechanisms that regulate neuronal gene expression is a major question in developmental biology and is crucial to understanding nervous system function. Better understanding of these mechanisms will also impact our understanding of neurological and psychiatric disorders associated with improper neural gene expression, such as autism and schizophrenia. The nematode C. elegans is an excellent model for the study of gene expression in the developing nervous system. The C. elegans nervous system comprises diverse neuron types that use conserved factors to regulate gene expression. Gene expression in many neuron-types can be monitored in vivo using fluorescent reporter transgenes, which allows the use of powerful genetic methods to discover factors required for neural gene expression. Such an approach identified the p38 MAP kinase (MAPK), PMK-3, as a factor required for proper gene expression and differentiation of a pair of C. elegans chemosensory neurons. We have found that mutations that block neurosecretion and neural excitability restore neural gene expression to p38 MAPK mutants, suggesting that neural activity antagonistically regulates p38 MAPK-dependent gene expression that promotes neurodifferentiation. This proposal will determine how neurosecretion and neural activity antagonize gene expression that defines a specific neuronal fate. Because activity-regulated gene expression is critical for the development and function of neural circuits, these studies will advance understanding of processes fundamental to brain function and whose dysfunction has been linked to neurological and psychiatric disorders.