Mechanisms of Neuronal Wiring and Rewiring in C. elegans

Establishment of a proper neuronal network during development and restoration of the network after an injury are critical for function of the nervous system. Despite significant progress in the research over the past few decades, much remains to be understood on the cellular and molecular mechanisms that control neuronal connectivity and regeneration. The studies in this thesis present timing mechanisms of dendrite arborization during development and two different functions of a scavenger receptor in debris removal and neuronal regeneration after an injury using cell and molecular biological and genetic approaches in C. elegans. Dendrite arborization of a nociceptive neuron, PVD neurons, occurs within a specific time frame during development. However, it remains unknown how the beginning and the end of the process are temporally controlled with such precision. We show that the lin-4-lin-14 regulatory circuit initiates the dendrite outgrowth early in development, whereas the lin-28-let-7-lin-41 regulatory circuit terminates the dendrite outgrowth at the final stage of development. The regulatory circuits control dendrite growth ability through antagonistic regulation of DMA-1, a transmembrane receptor on PVD dendrites. The LIN-14 transcription factor is likely to directly repress the transcription of dma-1, while the LIN-41 tripartite motif protein is likely to indirectly increase the DMA-1 protein level through a post-transcriptional means. Debris removal and neuronal regeneration occur following an injury in the C. elegans peripheral nervous system. However, the relationship between these events has yet to be determined. We demonstrate that debris removal is not a prerequisite for neuronal regeneration, and thus these two events are separable. Our results indicate that two distinct mechanisms mediate clearance of debris and promotion of neuronal regeneration by the CED-1 transmembrane receptor, a homolog of Draper and MEGF10. Both the extracellular and intracellular domains of CED-1 on the muscle-type engulfing cells play roles in debris removal by acting as a scavenger receptor. In contrast, the extracellular domain of CED-1 on the muscle-type engulfing cells promotes axon regeneration by acting as an adhesion molecule. The findings of these two studies provide further insights into the mechanisms underlying the formation and recovery of neuronal network.