Neuronal-specific gene expression--the interaction of both positive and negative transcriptional regulators

Gene expression patterns in neurons are complex and are modulated in response to multiple extracellular stimuli. In addition, during development and as neurons differentiate into distinct neuronal phenotypes, there is a co-ordinated activation and repression of a variety of genes. It is becoming increasingly evident that negative regulatory elements are present in neuronal-specific promoters. These elements have been shown, in part, to restrict promoter activity to the correct physiological cell type, both in transient transfection and in transgenic mouse models. Repression can be effected by different mechanisms depending on location within the promoter of silencer complexes and their relationship to other bound transcription factors. This review will discuss the molecular mechanisms regulating promoter function, in particular: (1) the combinatorial interaction between transcription factors which generate regulated promoter function; and (2) the restriction of promoter function to the correct cell type by bound repressor molecules. Determination of the mechanism of regulated gene expression will allow advances in gene therapy and definition of novel targets for pharmaceutical intervention. At the more basic level, functional dissection of the promoters of specific neuronal expressed genes will provide information of importance in two key areas of neurobiology: (1) the mechanism by which extracellular factors, such as neurotrophins and cytokines, regulate gene expression; (2) the events which lead to the tissue-specific expression of genes in subpopulations of neurons, both in the adult and during development.