Growth factor regulation of early growth response factor 3 localization and function in neurons
Kim, Julia Heewon
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The brain is a complex system of membrane-dependent cellular responses that utilize flexible and adaptive regulatory cascades to represent the presence or absence of extracellular signals. Many neurological diseases occur due to the sustained activation of signaling pathways that disturb important gene regulatory networks. Our initial studies have focused on temporal lobe epilepsy (TLE) where balance between excitatory and inhibitory synaptic transmission is most affected. Using in vitro and in vivo models of TLE, the Russek and Brooks-Kayal laboratories identified a crucial role for altered GABA-A receptor function that occurs in response to increased levels of α4 subunits. Increases in α4 are controlled by brain-derived neurotrophic factor (BDNF) and synthesis of early growth response factor 3 (Egr3), transcriptional activator of the a4 subunit gene. In the work of this thesis, we show that Egr3 also regulates expression of the excitatory n-methyl-D-aspartate receptor type 1 subunit (NMDAR1), providing an additional mechanism for increased synaptic activity associated with epileptogenesis. Recent evidence suggests that in addition to epilepsy, Egr3 plays a role in complex brain disorders, like schizophrenia and depression. Expression of Egr3 is critical for spatial memory like other important activity-dependent molecules such as cyclic adenosine monophosphate (cAMP)-response element-binding protein (CREB). Unlike these molecules that are found predominantly in the nucleus, this thesis reports that Egr3 may play a unique role in activity-dependent gene expression based on its unique cytoplasmic presence. Furthermore, mutation in the T12 residue of Egr3 that abolishes a putative protein kinase C/mitogen activated protein kinase (PKC/MAPK) phosphorylation site confers BDNF-induced regulation that is relevant to endogenous NMDAR1 gene expression. These results are the first demonstration that post-translational modification of Egr3 may be an important feature of its gene regulatory function. Taken together with the novel detection of Egr3 in putative synapses, this thesis opens a new area for investigation that considers the role of phosphorylation in the marking and trafficking of Egr3 within neuronal processes. It is hoped that future studies into the mechanism that controls Egr3 synaptic presence will uncover new opportunities for therapeutic intervention and early detection of disease.
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