Molecular studies of Caenorhabditis elegans dauer formation in the last two decades have revealed that three functionally overlapping neural pathways, TGF-?, cyclic GMP, and IGF, control the developmental response to dauer-inducing environmental cues, such as starvation and high dauer pheromone concentrations. Recently, it has been shown that autophagy is essential for dauer morphogenesis, fat accumulation and increased adult lifespan of mutants with reduced IGF signaling activity. Autophagy is an evolutionarily conserved lysosomal degradation pathway that is present in all eukaryotic cells and conserved from yeast to humans. However, it is unknown how the extracellular signals regulate autophagy activity within different tissues during dauer formation and whether autophagy functions cell-autonomously or non-autonomously in this developmental process. Our preliminary data shows for the first time that autophagy activity in neurons and intestinal cells plays a major role in regulation of adult lifespan, fat metabolism and dauer recovery, suggesting autophagy controls these phenotypes cell non-autonomously. Mutations in the autophagy gene atg-18 completely block the recovery of mutant dauer larvae with reduced IGF signaling, which reveals a novel function of autophagy in dauer recovery. The recovery from the dauer stage must be equally tightly controlled so that the post-dauer larva can resume its reproductive developmental program and produce progeny in a suitable environment. However, little information is known about how C. elegans recovers from the dauer stage. We hypothesize that autophagy in neurons and intestinal cells is an essential cellular process regulated by different signaling pathways to control dauer recovery and autophagy is involved in generation of a signal that can coordinate dauer recovery. In this proposal, we will integrate biochemical and genetic approaches to elucidate the role of autophagy in dauer recovery. Interestingly, it has been reported that autophagy is essential for stress-induced differentiation and development in different model systems such as Saccharomyces cerevisiae and Dictyostelium discoideum. Elucidation of the function of autophagy in dauer formation will shed light on the understanding of this stress-induced development response in different organisms including mammals.
Animal development is a complex process that involves hierarchical gene regulatory networks and understanding these gene networks has implications for the treatment of human disease. In the last two decades, the molecular study of the C. elegans dauer formation has greatly helped identify new components in the transforming growth factor-? (TGF-??) and insulin-like growth factor (IGF) signaling pathways. We recently discovered a novel function of autophagy, an evolutionarily conserved lysosomal degradation pathway, in controlling C. elegans dauer recovery. In this proposal, we will investigate the mechanism by which autophagy controls recovery of mutant dauer larvae with dysfunctional TGF-?? and IGF signaling pathways. Interestingly, dysregulation of autophagy, and both TGF-?? and IGF signaling pathways have been linked to aging, cancer and neurodegeneration diseases. Elucidation of the interactions between autophagy and these signaling pathways will enhance our understanding of the role of these pathways in controlling vertebrate development and the pathogenesis of human diseases.
