Transcription factors play essential roles in the processes of neuronal cell fate determination and expression of the mature neuronal phenotype that are necessary for normal development and function of the brain. My laboratory is investigating expression of the cyclin-dependent kinase 5 (cdk5) activator p35 as a model to understand the molecular mechanisms of cell type-specific transcription in neurons. The heterodimeric cdk5/p35 kinase plays a role in many neuronal processes ranging from neuronal migration and axon guidance to synaptic plasticity and drug addiction. Furthermore, improper cdk5 activity, caused by association with a proteolytic fragment of p35, has been implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's and amyotrophic lateral sclerosis. A repeated GC box element in the p35 promoter is necessary and sufficient for neuron-specific gene expression. The studies described in this proposal are designed to test the hypothesis that the mechanisms that regulate the levels and activity of the GC box-binding transcription factors Sp1, Sp3 and Sp4 during neurogenesis contribute to neuronal-specific expression of p35.
The specific aims of this research are to (1) determine which Sp transcription factors are important for GC box-dependent expression of p35 in neurons, (2) determine the mechanisms that regulate Sp transcription factor stability during neurogenesis, and (3) determine how SUMO-1 mediated repression of Sp3 is relieved in post-mitotic neurons. In addition to advancing our specific knowledge of the transcriptional mechanisms that regulate activity of the cdk5/p35 kinase, these studies will provide a paradigm for understanding how cell type-specific regulation of transcription factor levels and activity controls neuronal specific expression of many genes whose expression depends on GC box promoter elements. Since disturbances of the finely tuned transcriptional program in neurons are associated with developmental abnormalities and disease, it is imperative to increase our understanding of the molecular mechanisms that underlie cell type-specific gene expression in neurons.
