HYPERTROPHIC GROWTH AND METABOLISM


Recently, we have embarked on a new area, to study the role of the digestive tract for nutritional sensing during the worm's post-embryonic life. The discovery that factors controlling energy metabolism are conserved between mammals and C. elegans has provided a new and powerful strategy to delineate the molecular pathways that coordinate organismal growth and nutrition (6). Despite its simple organization, the nematode digestive tract is equipped to respond to food availability. Worms can adjust their rate of feeding, their energy source and, most dramatically, their development and growth. While previous studies focused on neuroendocrine circuits for food sensation (6), we believe the C. elegans digestive tract may be an important signalling center as well (47; Overfield and Mango, unpublished). Our goal is to elucidate the transcriptional response of the digestive tract to metabolic cues. We have discovered that PHA-4/FoxA and the nuclear hormone receptor DAF-12 are two important mediators of nutritional sensing in the pharynxF. Reduction of pha-4 activity in larvae or unliganded DAF-12 promote a starvation response while active PHA-4 and liganded DAF-12 favor growth. How do these factors sense food? We will distinguish between two models: that the level or activity of these proteins responds to a metabolite generated during digestion or alternatively, that these factors are modulated by neuroendocrine signalling pathways. Understanding the interplay of the digestive tract transcription factors, their upstream modulators and downstream target genes will enable us to map out how sensing food availability is coupled to organismal growth.