UC San Diego

Organisms endure environmental and internal perturbations throughout their lifetime. Environmental cues are integrated by the sensory neuron endings. Within the nervous system, the conserved MAPKKK DLKs play key roles in response to a variety of cellular stress, physical injury and pathological conditions. Previous studies have shown that regulation of DLK protein expression and activity in axonal compartments is pivotal in neuronal development, maintenance and stress response. However, it remains unclear whether DLKs may function in the sensory neuron endings. Moreover, experimental evidence that examines expression of DLKs is mostly based on overexpression approaches; how endogenously expressed DLKs are regulated remains elusive. The goal of my dissertation research focuses on identifying novel regulators of DLK-1 in C. elegans model, starting with a visual genetic screen for mutations altering the expression of endogenously GFP-tagged DLK-1. The first chapter of this dissertation summarizes the previously characterized cellular pathways that regulate DLKs level or activity in neurons. In the second chapter, I investigate the roles of a major group of mutations that affect the intraflagellar transport (IFT) and show that IFT actively controls DLK-1 levels in sensory cilia. Upon IFT disruption, DLK-1 triggers downstream signaling, which in turn represses dlk-1 transcription in sensory neurons. This IFT-dependent DLK-1 signaling protects cilia from degeneration, revealing a surveillance mechanism at the sensory endings of the organism. In the third chapter, I report the design of the genetic screen and phenotypes of additional mutants that specifically alter DLK-1 level in ciliated sensory neurons and are involved in multiple ciliary processes including anterograde IFT transport, BBSome, MAP kinase and olfactory signaling, and repress DLK-1 expression in a cell type-specific manner. Taken together, my dissertation establishes the methodology to uncover and also identifies new mechanisms regulating the stress responsive DLK signaling at sensory endings of the nervous system.