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Publisher Summary This chapter focuses on the regulation of TH expression by stimuli that activate transsynaptic mechanisms and by cell-cell contact. The chapter discusses the evidence supporting the hypothesis that these stimuli activate TH gene transcription rate and summarize some of the available information concerning the mechanisms responsible for this transcriptional regulation. Studies from numerous laboratories showed that this transsynaptic induction of TH required 2–4 hr of prolonged stress, occurred slowly over 12–24 hr, was because of an increase in TH protein and TH mRNA, and was mediated by nicotinic cholinergic receptors. More recently, the laboratory used nuclear run-on assays to test whether these transsynaptic increases in TH expression were because of initial increases in TH gene transcription rate. During development of the autonomic nervous system, neuroblasts migrate from the neural crest to the sites of primitive sympathetic ganglia, where they aggregate and TH expression is first observed. Many environmental cues are thought to participate in this initial expression of TH and in maintaining its basal expression; one of these cues is increased cell–cell contact. Transsynaptic regulation of the TH gene is mediated by both cholinergic and noncholinergic receptors; hence, multiple signaling pathways also regulate the gene. Three major second messengers have been implicated in this response: cyclic adenosine monophosphate (cAMP), diacylglycerol, and calcium. Each of these second messengers stimulates TH gene transcription rate and induces TH mRNA and TH protein in cultured cells. The participating transcription factors and the precise molecular steps in the signaling pathways remain to be elucidated. |
