Controlling the expression of the TAC1 gene is crucial to controlling fear, anxiety and depression. TAC1 codes for the protein Substance P; a small neuropeptide that is involved in modulating anxiety and depression states. Mouse knockout studies were the Substance P receptor (NK1) function is lost, show animals with reduced fear and anxiety responses and more aggression than wild type mice. High levels of Substance P and NK1 receptor are also present in the amygdala, and exposing rodents to stress increases the expression of TAC1 markedly within the amygdala compared to wild type animals. Despite an understanding of the role of Substance P in the brain, almost nothing is understood about the way this gene is controlled both in a tissue specific manner and in response to various stimuli, such as stress or pain. With this in mind, our lab has identified a remote enhancer to the TAC1 gene, termed ECR1. This enhancer is able to drive expression of a LacZ reporter construct in transgenic mice, and is only active in the amygdalaloidal regions of the brain. We have identified numerous evolutionarily conserved transcription factor binding sequences within ECR1 that may play a role in the expression of the TAC1 gene. Analysis of ECR1 DNA sequences from many species shows an almost complete conservation of the sequence throughout vertebrate evolution; with ECR1 being conserved all the way back to chicken. This equates to ECR1 being conserved across 300 million years of evolution. It is believed that the transcription factors controlling ECR1 activity are in turn controlled by signal transduction mechanisms that may involve many pathways such as PKA, PKC, and MAPKs. Using a unique combination of bioinformatics, transgenics, organotypic culture and protein-DNA interaction techniques we have begun to dissect the mechanisms that underlie ECR1 activity. In understanding these mechanisms it is hoped that new and potentially clinical targets for novel therapies to disorders such as anxiety and depression can be identified.
|Publication status||Published - 6 Jun 2006|
|Event||Mechanisms Underlying Emerging Themes in Neurobiology - University College Cork, Cork, Ireland|
Duration: 6 Jun 2006 → 7 Jun 2006
|Conference||Mechanisms Underlying Emerging Themes in Neurobiology|
|Period||6/06/06 → 7/06/06|