Molecular mechanisms that regulate p38 MAPK-dependent neuronal gene expression

项目摘要。神经系统包括各种各样的神经元细胞类型。一 分化的神经元类型由决定其形态的独特基因表达模式定义， 连接性和功能。破译调节神经元基因表达的发育机制是 这是发育生物学中的一个主要问题，对理解神经系统功能至关重要。更好 对这些机制的理解也将影响我们对神经和精神疾病的理解。 与神经基因表达不当相关的疾病，如自闭症和精神分裂症。线虫 C.线虫是研究发育中神经系统基因表达的极好模型。梭 线虫的神经系统包括多种神经元类型，这些神经元类型使用保守因子来调节基因， 表情在许多神经元类型的基因表达可以监测体内使用荧光报告 转基因，它允许使用强大的遗传方法来发现神经基因所需的因素， 表情这种方法确定了p38 MAP激酶（MAPK），PMK-3，作为一个因素所需的适当 基因表达和分化的一对C.线虫化学感受神经元我们发现 阻断神经分泌和神经兴奋性的突变恢复p38 MAPK的神经基因表达 突变体，表明神经活性拮抗性调节p38 MAPK依赖性基因表达， 促进神经分化。这项提议将确定神经分泌和神经活动如何拮抗 基因表达决定了特定的神经元命运。因为活性调节的基因表达对于 神经回路的发展和功能，这些研究将促进对过程的理解， 大脑功能的基础，其功能障碍与神经和精神疾病有关。

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.