An important goal for regenerative medicine is to understand how neurons sense and respond to axonal damage. Due to the highly polarized structure of axons, axonal transport machinery, which delivers cellular cargo from one part of the axon to the other, plays important roles in the cellular responses to injury. One major response is the induction of new axonal growth. This regenerative response requires the retrograde transport of signaling molecules from the injury site to the nucleus. Another major response is degeneration of the severed distal 'stump'. This may also rely on axonal transport machinery, since defects in the process of axonal transport usually accompany (and often proceed) axonal degeneration in neurodegenerative disorders. To study mechanisms of injury signaling, degeneration, and axonal transport, we take advantage of the powerful genetics of Drosophila as a model organism, in which we have developed a new injury paradigm that allows mechanistic characterization of injury response pathways in vivo. Our assays include nuclear reporters, which measure changes in gene expression in injured neurons, and live imaging assays that measure axonal transport of specific cargo in axons. The focus of this study is the role and mechanism of a conserved axonal kinase, named Wallenda (Wnd) in Drosophila, DLK in vertebrates. Recent studies indicate that this kinase regulates both regenerative and degenerative responses to axonal injury. Our recent observations suggest that Wnd may function by regulating the transport of specific cargo in axons. The goals of this study are to identify the Wnd-regulated cargo, and determine the role(s) of this cargo in both retrograde signaling and degeneration.

Public Health Relevance

Axonal damage triggers both regenerative and degenerative responses in neurons. We are studying a molecular pathway, which has recently been discovered to function in both the regrowth of axons after injury and also in degeneration of the part of the axon that has been severed from the cell body. The findings from this work will be important both for treatment of spinal cord injuries and also for understanding mechanisms of neurodegenerative disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Owens, David F
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University of Michigan Ann Arbor
Schools of Arts and Sciences
Ann Arbor
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Hao, Yan; Frey, Erin; Yoon, Choya et al. (2016) An evolutionarily conserved mechanism for cAMP elicited axonal regeneration involves direct activation of the dual leucine zipper kinase DLK. Elife 5:
Siebert, Matthias; Böhme, Mathias A; Driller, Jan H et al. (2015) A high affinity RIM-binding protein/Aplip1 interaction prevents the formation of ectopic axonal active zones. Elife 4:
Wong, Ching-On; Palmieri, Michela; Li, Jiaxing et al. (2015) Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction. Cell Rep 12:2009-20
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Klinedinst, Susan; Wang, Xin; Xiong, Xin et al. (2013) Independent pathways downstream of the Wnd/DLK MAPKKK regulate synaptic structure, axonal transport, and injury signaling. J Neurosci 33:12764-78
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Xiong, Xin; Hao, Yan; Sun, Kan et al. (2012) The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein. PLoS Biol 10:e1001440

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