The Roles of PHR and DLK in Axon Development and Post-Injury Responses
Date of Award
Doctor of Philosophy (PhD)
Axonal connectivity is established by regulated guidance of growing axons during development and maintained by proper neuronal responses to damage in adult organisms. This study investigates different aspects of axonal biology that are required for integrity of axons: axon guidance, axon regeneration, and axon degeneration.
During development, axons often form synapses with multiple targets by extending branches along different paths. We demonstrate that Highwire, the Drosophila member of PHR family ubiquitin ligases, is required for the segregation of sister axons in the developing Drosophila brain. Loss of highwire leads to thinning and shortening of the axonal lobes in the mushroom body, due to guidance errors following axon branching. We show that elevation in the level of the MAPKKK dual leucine zipper kinase (DLK), a previously identified substrate of Highwire, is responsible for the highwire phenotype. Genetic studies demonstrate a non cell-autonomous role of Highwire and also suggest that Plexin A signals may interact with Highwire to regulate axonal guidance.
We next study how axons react to injury to restore neural function. When axons are severed by injury, distal axons degenerate whereas proximal axon stumps sometimes regenerate and re-build the functional connectivity. We show that DLK promotes injury-induced regeneration (pre-conditioning effect) of axons following peripheral nerve injury in mice. DLK is required for retrograde transport of axon injury signaling components to the cell body and promotes upregulation of pro-regenerative transcription factors. These data demonstrate that DLK regulates early responses to injury that subsequently reprogram a neuron to better regenerate.
Axon degeneration is a consequence of a variety of neurological disorders as well as traumatic injury. The c-Jun N-terminal kinase (JNK) pathway is required for axonal destruction shortly after axonal injury. We identify superior cervical ganglion 10 (SCG10) as an axonal JNK substrate during axon degeneration. SCG10 undergoes fast turnover and replenishment by axon transport in healthy axons. Following axotomy SCG10 is rapidly lost from distal axons due to the lack of supply from the cell body. SCG10 degradation requires JNK activity in both injured and uninjured axons. We show that SCG10 loss is functionally important because preservation of SCG10 is sufficient to delay axon fragmentation.
Chair and Committee
Valeria Cavalli, Robert W Gereau, Timothy M Miller, Kelly R Monk, Paul H Taghert
Shin, Jung Eun, "The Roles of PHR and DLK in Axon Development and Post-Injury Responses" (2012). Arts & Sciences Electronic Theses and Dissertations. 95.