Establishment of the neuronal network is essential for brain function. This multifaceted process requires intricate regulation of gene expression through both transcriptional and post-transcriptional mechanisms. In particular, post-transcriptional regulation of mRNAs offers the advantage of rapid and local control of the cellular proteome. Such sophisticated regulation depends on both cis-regulatory elements and trans-acting factors, such as RNA-binding proteins (RBPs) and miRNAs. One key factor for neuronal development and function is the RBP, HuD, which binds target mRNAs to regulate stability and translation. The list of HuD ligands is rapidly expanding. However, how HuD regulates mRNA targets in vivo to coordinate sophisticated biological paradigms is unknown. In this dissertation we uncover HuD-dependent post-transcriptional regulation of two key pathways for neuronal development and function. We show that HuD selectively binds and stabilizes an mRNA isoform of the brain derived neurotrophic factor (BDNF) and therefore promotes expression of BDNF protein to be transported to hippocampal mossy fiber axonal boutons. We also discovered that post-transcriptional regulation by a HuD-miRNA molecular loop selectively up-regulates a Cyclin-dependent kinase 5 (Cdk5) activator called p39. This selective regulation occurs concurrently with histone-acetylation-dependent transcription of p39, which enhances Cdk5 activity in the postnatal brain. We reveal essential functions of the Cdk5 activator p39 in neuronal network formation. Moreover, HuD-regulated Cdk5 signaling governs the projection of hippocampal mossy fiber axons. Given the functional interplay between BDNF and Cdk5 signaling, the cooperative regulation of both pathways by HuD revealed by our studies provides an intriguing example of higher-order coordination of gene networks. Thus, these studies advance our understanding of how post-transcriptional regulation is employed to govern multifaceted aspects of neuronal function in the brain.
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