The dynamic gut: nutrient regulation of aging and development by PHA-4/FOXA

The gastrointestinal (GI) tract is a central player in the regulation of development and aging. FoxA factors are master regulators of the GI tract during embryogenesis and after birth but little is know about their regulation. I use the simple digestive tract of C. elegans to investigate the role of pha-4/FoxA in whole organism responses to nutrients. My search for pha-4/FoxA regulators has lead to insights regarding how an animal responds to nutrients during aging in the adult and postembryonic development. I have examined the role of pha-4/FoxA during adult lifespan extension due to loss of nutrient signaling through the Target of Rapamycin (TOR) pathway. To search for regulators of pha-4/FoxA, Dustin Updike performed a genetic screen to search for suppressors of the larval lethality associated with the pha-4 mutation and discovered an AAA ATPase, ruvb-1, as apotent suppressor. I showed that the ruvb-1 mutant phenocopies mutations in the TOR pathway suggesting that these genes have a similar function in protein biosynthesis. I found that pha-4/FoxA is required for extension of adult lifespan by loss of CeTOR signaling; however, only mutations in one of the predicted CeTOR targets, rsks-l/S6K, required pha-4/FoxA for lifespan regulation. These data suggest a model where TOR signaling through S6 kinase antagonizes pha-4/FoxA factor activity. Secondly, I have investigated the role of pha-4/FoxA during L1 diapause induced by starvation. Proper developmental arrest in response to starvation has been shown to be required for survival however little is known about factors that are required during L1 diapause. I showed that pha-4/FoxA is require d for L1 diapause survival post embryonically. I showed that levels of PHA-4 are important for starvation survival. pha-4/FoxA is required for initiation of development after periods of starvation and is not required for developmental arrest during starvation. We a recurrently using genomewide approaches to determine targets of pha-4/FoxA that a reimportant for L1 diapause recovery. This work investigates how nutrients regulate whole body responses through the GI tract. I find that pha-4/FoxA plays critical roles in coupling low nutrient intake to aging and development.