Signal‐dependent Regulation of Transcription Factor Activity

Abstract

Signal dependent regulation of transcription factor activity in the nervous system controls gene expression programs that underlie learning and memory. Transcription factor Sp4 is zinc finger DNA binding protein that regulates neuronal connectivity, brain development and function. In humans, altered Sp4 has been linked to psychiatric disorders such as schizophrenia and bipolar disorder. We are investigating the function and regulation of Sp4 in neurons. Our recent studies have revealed two distinct calcium‐dependent signaling pathways that regulate Sp4 via altered patterns of post‐translational modification. We have found that stimulation of the NMDA receptor activates a PP1/PP2A protein phosphatase signaling pathway that dephosphorylates Sp4. Our data suggests that this phosphorylation reduces Sp4 function independent of an effect on Sp4 levels. We have also found that Sp4 protein, but not mRNA, abundance is highly regulated in response to changes in membrane potential associated with neuronal activity. In resting neurons, Sp4 is ubiquitinated and rapidly degraded by the proteasome. We have found that calcium influx via store operated calcium entry (SOCE) and the ER calcium sensor Stim1 regulates Sp4 ubiquitination. Our studies reveal new aspects of the complex mechanisms that determine signal‐dependent regulation of transcription factor activity important for neuronal plasticity, brain development and disease.