Mutations in transcription regulators that play a role in activity-dependent induction of gene expression in neurons are strongly linked to human cognitive disorders. For example, the pathogenesis of Rett-syndrome and Rubenstein-Taybi syndrome result from mutations in the transcription factor MeCP2 and the transcription co-activator CBP, respectively. However, little is known on how specific gene expression patterns are induced in response to neuronal stimulation. Therefore, an identification of the transcription factors that regulate activity dependent gene expression would guide more selective strategies for developing therapies for human cognitive disorders. In this proposal we will use electrophysiology, molecular genetics and Epigenomics techniques to test the hypothesis that the novel uncharacterized protein PRR7 controls gene expression in response to synaptic stimuli and also regulates synaptic function. PRR7 was identified in a screen for postsynaptic density proteins that contain a nuclear localization sequence (NLS) to identify proteins that could serve as synapse-to-nucleus messengers. We will determine the role of PRR7 in synaptic function by examining spontaneous synaptic activity in cultured neurons lacking and overexpressing PRR7. To evaluate the role of PRR7 as a transcription factor we will test its ability to bind specifically to DNA and activate gene transcription using a Luciferase reporter assay. With the experiments described here, we will determine if PRR7 is a neuronal transcription factor and a regulator of synaptic function in mammalian brain. This study will increase our knowledge of the transcription factors that regulate synaptic strength, which is essential for proper brain function.
The pathogenesis of human cognitive disorders is strongly linked to mutations in transcription factors that play a role in activity-dependent regulation of gene expression in neurons. For example, Rett-syndrome and Rubenstein-Taybi syndrome result from mutations in the transcription factors MeCP2 and CBP, respectively. In this proposal we will test the hypothesis that the novel uncharacterized protein PRR7 is a transcription factor in neurons that controls gene expression to regulate synaptic function, which is essential for proper brain function.
| Kravchick, Dana O; Karpova, Anna; Hrdinka, Matous et al. (2016) Synaptonuclear messenger PRR7 inhibits c-Jun ubiquitination and regulates NMDA-mediated excitotoxicity. EMBO J 35:1923-34 |
