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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurogenesis and Cell Fate Study Section (NCF)
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Riddle, Robert D
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University of New Mexico
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