Regulation of Regenerative and Degenerative Responses to Axonal Injury

[摘要] Axons allow neurons to communicate over long distances, however their long length makes them vulnerable to injury, since damage at any location leads to loss of a neuron’s function within a circuit. Repair from axonal damage requires that damaged axon gains an ability to initiate new growth which is termed axonal regeneration. This involves the activation of signaling pathways in the injured neurons which promote a ;;regenerative’ state, but many neuronal types in the mammalian central nervous system show a failure to initiate this state. Functional repair also requires that the distal axonal stumps, which have lost connection with cell bodies hence are non-functional, undergo degeneration and clearance via a process termed Wallerian degeneration. This degeneration takes place via a cell autonomous self-destructive pathway, akin to apoptosis, but with distinct, and still poorly characterized molecular components.My thesis work has focused on understanding the cellular mechanisms by which neurons detect and respond to axonal damage. A conserved axonal kinase, named DLK in mammals or Wallenda (Wnd) in Drosophila, appears to function as a ;;sensor’ of axonal damage in neurons.However, the mechanism that activates Wnd/DLK is unknown. I have discovered that the cAMP-regulated protein kinase A (PKA) is a conserved and direct upstream activator of Wnd/DLK: PKA is required for the induction of Wnd/DLK signaling in injured axons, and directly stimulates its activation via phosphorylation of its activation loop. Elevation of intracellular cAMP level is a broadly known but poorly understood method to stimulate the growth potential of axons. In this study, I found that DLK is essential for the regenerative effects of cAMP. These findings link two important mediators, DLK/Wnd and cAMP/PKA, into a unified and evolutionarily conserved molecular pathway for regulating axonal regeneration upon axonal injury. My work has also identified a new regulator of Wallerian degeneration, from the fortuitous discovery of a mutation that strongly inhibited axonal degeneration in the strain background of dcp-1 mutant. Genetic mapping, whole genome sequencing and rescue analysis pinpoint this phenotype to a mutation in the putative transmembrane protein, Raw. Raw functions as a negative regulator of the transcription factor AP-1, and this activity mediates its role in axonal degeneration. While Raw does not have an obvious mammalian homologue, the basic mechanism of axonal degeneration is highly conserved between Drosophila and mammalian neurons, so understanding the mechanism for Raw in degeneration may lead to new insight for understanding and treating nerve damage in humans.

[发布机构] University of Michigan

[效力级别] axon degeneration

[关键词] axon regeneration;axon degeneration;Molecular;Cellular and Developmental Biology;Science;Molecular, Cellular, and Developmental Biology