The Role of Coronin-1 in Neurotrophin Signaling During Sympathetic Nervous System Development
Suo, Dong, Biology - Graduate School of Arts and Sciences, University of Virginia
Deppmann, Christopher, Department of Biology, University of Virginia
Long-distance signaling is a property inherent to neurons and neural circuits. Communication between axonal targets and neuronal cell bodies is increasingly recognized as critical for developmental processes and for normal function in adulthood. How this retrograde long-distance signal maintains high fidelity as it traffics to the cell body remains unknown, but could be achieved by the enhanced signal durations observed in some growth factor signaling. I found that the retrograde Nerve growth factor (NGF)-TrkA signaling endosome recruits a novel effector protein known as Coronin-1, which protects the endosome from lysosomal degradation during development. Indeed, in the absence of Coronin-1, the NGF-TrkA signaling endosome fuses to lysosomes 6-10-fold faster than in wild-type neurons. Furthermore, loss of Coronin-1 affects several NGF-dependent processes including neuron survival. These phenotypes are consistent with the finding that Coronin-1 stabilizes the NGF-TrkA signaling endosome, providing a plausible mechanism for long-distance retrograde signaling. Further, I demonstrated that Coronin-1 protects the signaling endosome by facilitating NGF-dependent calcium release and subsequent calcineurin activation. This novel mechanism for NGF-dependent calcium release provides insight into the mechanistic details underlying NGF-dependent transcription, axon growth, and cell survival. Above all, my findings argue for a critical role for Coronin-1 in sympathetic nervous system development. In addition, to investigate the process by which neurotrophins direct neuronal survival, I examined another key developmental process mediated by neurotrophic factors: the molecular mechanisms governing how axons traverse distinct axon growth environments/niches. The neurotrophins, NT3 and NGF are derived, respectively, from intermediate targets such as blood vessels and final targets such as heart. Both NT3 and NGF are critical for proper development of the sympathetic nervous system, and interestingly both signal through the TrkA receptor tyrosine kinase. Given that both NT3 and NGF promote axon growth, the question remains: how do sympathetic axons switch preference from intermediate to final target fields in order to form an intergraded circuit? One might argue that since NGF-TrkA, but not NT3-TrkA, undergoes retrograde signaling to induce transcriptional programs, the mechanistic switch may be linked to NGF-dependent transcription. Coronin-1 represents an NGF-induced gene that may mediate this transition. Using in vivo and in vitro axon growth assays I demonstrate opposing roles of Coronin-1 in NGF versus NT3 mediated signaling and axon extension. This provides critical insight into the mechanisms underlying the transition of axons from intermediate to final targets during development.
PHD (Doctor of Philosophy)
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