Roles for the Highwire/Wallenda Pathway in Regenerative and Degenerative Responses to Axonal Injury.

Axons allow neurons to communicate over long distances, and their long length makes them vulnerable to injury. Neurons make several important responses to axonal injury. One is that the axons that are still connected to the cell body can initiate new axonal growth. This requires transcriptional reprogramming, and an important question is how this nuclear event can be induced by an injury in a distal site of the axon. Another response is that the distal stump, which is disconnected from the cell body, degenerates through a process called Wallerian degeneration. This self-destruction process is poorly understood, but is misregulated in some neurodegenerative diseases. To study these responses in a model organism, I developed an axonal injury assay in Drosophila. I have characterized the function an axonal signaling pathway, which is regulated by the ubiquitin ligase Hiw, and its conserved axonal target, Wnd. I found that Hiw and Wnd, through a downstream signaling cascade, regulate several important responses to axonal injury. First, the Hiw/Wnd signaling pathway is activated by axonal injury and mediates the transcriptional changes that facilitate new axonal growth from the proximal stump. Second, this signaling pathway also inhibits Wallerian degeneration, allowing for neurons that have been injured once to have increased resilience to a second injury. This demonstrates that Hiw and Wnd control remarkable plasticity in the axonal degeneration process. Third, Hiw performs an additional role in degeneration by regulating the levels and localization of NMNAT. This NAD+ synthesizing enzyme plays an essential role in dramatic inhibition to degeneration when hiw is mutant. Since the Hiw/DLK pathway is highly conserved, these findings may ultimately be of clinical interest for understanding and treating nerve damage in humans.PHDMolecular, Cellular and Developmental BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/97796/1/xinxiong_1.pd