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Fenstermacher, Sara

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Fenstermacher

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Fenstermacher, Sara

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    From nucleus to axon: Spatial regulation of bclw mRNA promotes neurotrophin-dependent axon survival
    (2015-05-07) Fenstermacher, Sara; Ginty, David; Pecot, Matthew; Moore, Melissa
    During development, dorsal root ganglion (DRG) neurons depend on target-derived neurotrophins to establish a functional circuit capable of conveying sensory information to the central nervous system. Neurotrophins signal from the periphery via dynein-dependent retrograde transport of signaling endosomes to activate a nuclear transcriptional response critical for neuronal survival. Importantly, neurotrophins support the health of the entire DRG neuron, but it is not well understood how neurotrophins specifically function to promote survival of axons. Previous research demonstrated that target-derived neurotrophins induce expression of the anti-apoptotic Bcl2 family member, Bclw, and in vivo studies demonstrate that Bclw is a critical survival factor for sensory axons. Here we describe multi-step regulation of bclw mRNA from the nucleus to the axon to support the health and long-term maintenance of axons. We find that neurotrophins induce transcription of bclw mRNA, which is rapidly transported to axons. There it is locally translated to prevent caspase-dependent apoptosis and axon degeneration. We identify the RNA-binding protein splicing factor proline-glutamine rich (SFPQ) as a critical regulator that specifically interacts with bclw mRNA. SFPQ is required for nuclear export of bclw mRNA and for generating an axonal pool of bclw mRNA. Interestingly, we find that SFPQ binds and regulates additional mRNAs also required for axonal survival. Therefore we propose that SFPQ orchestrates an RNA regulon for coordinated regulation of functionally-related mRNAs including, bclw and laminb2, and thereby enables neurotrophin-dependent axonal health. Lastly, to investigate neurotrophin regulation of bclw translation in axons we describe development of a novel tool called spaceSTAMP. SpaceSTAMP allows for drug-dependent labeling of newly synthesized protein within distinct cellular compartments for both live cell imaging and biochemical analysis. We believe spaceSTAMP will be a rigorous method for studying local protein synthesis that will also provide critical information about the functional significance for localized translation in axons. Together, these studies demonstrate that spatial regulation of bclw mRNA mediates neurotrophin-dependent axonal viability and contribute towards our understanding of how neural circuits are established and maintained throughout life.