Extension and maturation of axons and dendrites are essential developmental steps that allow the nervous system to function. This development requires precise regulation of gene expression, with coordinated activation and inactivation of gene expression programs associated with growth, maturation, and function of neurons. Growth of neuronal processes or `neurites' must be precisely timed and regulated to generate functional neural circuits. Regulation of gene expression extends beyond transcribing DNA into mRNAs, and it has become increasingly clear that much regulation occurs post-transcriptionally in neurons. Regulatory steps include splicing, subcellular localization, and translational control of mRNAs. Stability of mRNAs plays a critical role in gene expression by modifying the amount of an individual mRNA available as a template for generating new protein over time. Stabilization and destabilization of mRNAs within growing neurites also impacts where new proteins are produced. Despite increased recognition of importance of this mechanism, we have little understanding of how neuronal mRNA stability is regulated. Recent work from the PI's and Co- PI's labs have uncovered a mechanism for modulation of mRNA stability in neurons. The RNA binding proteins KSRP and HuD compete for binding to GAP-43 mRNA. Both these RNA binding proteins are known to have multiple functions, and our data suggest that KSRP and HuD have antagonistic functions. For GAP-43 mRNA, KSRP binding destabilizes the transcript while HuD binding stabilizes the transcript. By initial CLIP analyses, KSRP and HuD can bind to overlapping cohorts of mRNAs and cytoplasmic KSRP appears to provide a governor to limit neurite length by destabilizing mRNAs. These data have led us to hypothesize that competitive interactions of HuD and KSRP with specific cohorts of ARE-containing mRNAs control the temporal and spatial pattern of neuronal protein expression during the initiation and termination of neurite outgrowth through changes in mRNA stability. We will test this hypothesis with three specific aims: 1) Does KSRP destabilize neuronal mRNA cohorts? 2) Do KSRP or HuD interactions alter stability of localized mRNAs? 3) Do KSRP and HuD compete for binding to a shared cohort of mRNAs with antagonistic functions? Completion of these aims will fill a gap in knowledge on mechanisms of neuronal mRNA stability and its contributions to brain development.
Correct wiring of the nervous system requires the extension of neuronal processes that connect individual neurons to their targets. This growth of neuronal processes is precisely regulated by changes in gene expression programs. We have little understanding of how stability of gene products is regulated and how this contributes to sculpting the connectivity of the brain. The studies here focus on the molecular mechanisms of this stability and how this impacts neuronal differentiation.
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