TRANSCRIPTIONAL CONTROL OF NEUROPEPTIDE GENE-EXPRESSION IN SENSORY NEURONS, USING THE PREPROTACHYKININ-A GENE AS A MODEL

Control of neuropeptide gene expression in sensory neurons is determin ed in part by a variety of tissue-specific, developmental, and stimulu s-induced transcription factors that interact with the promoters of th ese genes. We have analysed the regulation of the rat preprotachykinin -A (rPPT) gene, which is expressed in a subset of dorsal root ganglia neurons. A region of the promoter encompassing approximately 1300 base pairs spanning the transcriptional start site has been analysed in de tail both by functional analysis of promoter activity in clonal cell l ines and dorsal root ganglia neurons grown in culture and by in vitro characterisation of transcription factor interaction with this region. Interestingly our analysis indicates an important role in rPPT gene e xpression for the E box transcription factor family. This class of tra nscription factor has been demonstrated to be a major determinant of c alcitonin gene related peptide (CGRP) expression, which is also expres sed in dorsal root ganglia neurons often under similar conditions as r PPT. In addition, multiple regulatory domains have been identified in the rPPT promoter, which act as activators in a variety of cell types. These elements are silenced in the context of the rPPT promoter in ma ny non-neuronal cells. Therefore, tissue-specific expression of report er genes directed by the rPPT promoter in transient transfection is de termined in part by a variety of silencer elements, which act to repre ss the function of several domains that act as constitutive enhancers of expression in a wide range of cells. Removal or modulation of silen cer elements in the rPPT promoter allows activity in a wider variety o f cell types. We postulate that control of rPPT gene expression is the result of dynamic interplay of both positive and negative regulatory elements, a phenomenon observed in several other neuronal-specific gen es, including that encoding CGRP.