Besides transcription, post-transcriptional mechanisms, such as RNA processing, mRNA stability and local translation, are also important for controlling the expression of many nervous system-specific genes. For a large number of neuronal genes, expression levels are controlled by changes in mRNA stability. These processes are regulated by specific interactions between RNA-binding proteins and instability- conferring sequences in the mRNAs. One of the best characterized post-transcriptionally regulated genes in neurons is that for GAP-43. Work done under our previous grants demonstrated that GAP-43 gene expression is regulated by selective changes in the stability of its mRNA, and that this process depends on the interaction of a highly conserved regulatory element in the 3'untranslated region (3'UTR) of the mRNA with the neuronal-specific RNA-binding protein HuD. Not only is HuD capable of stabilizing GAP-43 mRNA in developing neurons in culture, but also overexpression of this protein in transgenic mice increases GAP-43 gene expression in the hippocampus and neocortex. We have recently found that the pro-destabilizing RNA-binding protein KSRP also binds to the GAP-43 mRNA, suggesting that this protein may be responsible for the fast degradation of the GAP-43 mRNA observed in mature dentate granule cells. Based upon our preliminary studies, we propose that the stability of GAP-43 and other post- transcriptionally-regulated neuronal genes is controlled by the interplay of pro-stabilization factors such as HuD and pro-degradation factors such as KSRP. To test this hypothesis, we plan to perform the studies under the following two specific aims:
Aim 1. To explore the mechanism by which HuD and KSRP control the stability of neuronal mRNAs.
Aim 2. To define the function of HuD and KSRP in the post-transcriptional control of neuronal gene expression in vivo during developmental and adult plasticity. Although the aims are focused on GAP-43, our studies will include other targets of HuD such as neuroserpin and tau. These mRNAs were chosen because they are axonally-localized, developmentally- regulated, upregulated in response to injury and thus, likely to be controlled by similar mechanisms. The proposed studies will characterize the mechanisms of control of GAP-43 and other post- transcriptionally-regulated neuronal mRNAs. Given the role of these proteins in nervous system development, synaptic plasticity, and nerve regeneration, the elucidation of regulatory mechanisms controlling their mRNAs has a broad range of potential applications, from the treatment of neurodevelopmental disorders to the recovery from brain trauma and spinal cord injury.
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