Transcriptional Mechanisms Regulating Activity Dependent

Child Health And Human Development

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Abstract

Epigenetic and genetic factors contribute to the remodeling of the nervous system and skeletal muscles during development. The properties of postsynaptic targets, largely determined by transcription, are modified by distinct patterns neural depolarization and the action of released neuronal factors. Cell lineage and developmental context contribute to the response elicited by these epigenetic factors. The Section on Molecular Neurobiology is interested in elucidating the molecular pathways that contribute to the activity-dependent developmental plasticity of neurons and skeletal muscles. To this end, we are studying the developmental regulation of NMDA receptors in central neurons and Troponin I in skeletal muscle. Activation of NMDA receptors (NRs) by the neurotransmitter glutamate is necessary for activity-dependent plasticity at numerous excitatory synapses. We have studied the regulation of the NR2A and NR2C subunits of the receptor. The NR2A basal promoter and adjacent sequences were cloned, tested for function. Transgenic mice harboring 9 kilobases of NR2A upstream sequence express the luciferase reporter specifically in neurons. Deletion analysis of constructs transfected into cortical neurons identified sequences important for developmental- and neuronal-specific transcription. Studies are in progress to identify factors regulating the developmental expression of NR2A. In other studies we found that expression of the NR2C gene in cerebellar granule cells is greatly enhanced by neural activity and Neuregulin (Nrg), a factor distantly related to the epidermal growth factor. Recently, other groups found that Nrg also regulates expression of neurotransmitter receptors for acetylcholine and GABA, as well as survival of glial cells. Because of the central role of Nrgs in CNS development, we are studying the regulation and contribution of these factors to synaptic plasticity. We found that the 3 Nrg genes (Nrg 1-3), as well as their four receptors (ErbB 1-4), have distinct regional and developmental expression patterns. Interestingly, NMDA and ErbB receptors are co-expressed at postsynaptic densities (PSD) where they interact with the same proteins harboring PDZ protein-protein interaction domains. The PDZ-domain proteins are important because they scaffold receptors and channels to signaling molecules, thus coupling synaptic activity to signaling cascades in the postsynaptic neurons. We are presently studying the importance of these interactions. To understand the signaling pathways that selectively regulate distinct muscle genes, we have identified and characterized the enhancers of the troponin I slow (TnIs) and fast (TnIf) genes. Our results suggest that a complex of transcription factors interact with these enhancers to regulate transcription. Using a yeast-1-hybrid system, we have isolated putative factors that confer muscle fiber-type-specificity. One of these factors, known as GTF-3, encodes a protein with 5-6 internal repeats that may interact with a series of transcription factors. Interestingly, the GTF-3 gene, as well another member of this gene family, is deleted in persons afflicted with the Williams-Beuren Syndrome (WBS) which results from a micro-deletion on chromosome 7q11.23. Persons with WBS are reported to have variable degrees of mental retardation, supra valvular aortic stenosis, and myopathies. Studies are in progress to understand the role of GTF-3 in the deficiencies associated with WBS.