Rictor/TORC2 mediates gut-to-brain signaling in the regulation of phenotypic plasticity in C. elegans

Animals integrate external cues with information about internal conditions such as metabolic state to execute the appropriate behavioral and developmental decisions. Information about food quality and quantity is assessed by the intestine and transmitted to modulate neuronal functions via mechanisms that are not fully understood. The conserved Target of Rapamycin complex 2 (TORC2) controls multiple processes in response to cellular stressors and growth factors. Here we show that TORC2 coordinates larval development and adult behaviors in response to environmental cues and feeding state in the bacterivorous nematode C. elegans. During development, pheromone, bacterial food, and temperature regulate expression of the daf-7 TGF-β and daf-28 insulin-like peptide in sensory neurons to promote a binary decision between reproductive growth and entry into the alternate dauer larval stage. We find that TORC2 acts in the intestine to regulate neuronal expression of both daf-7 and daf-28, which together reflect bacterial-diet dependent feeding status, thus providing a mechanism for integration of food signals with external cues in the regulation of neuroendocrine gene expression. In the adult, TORC2 similarly acts in the intestine to modulate food-regulated foraging behaviors via a PDF-2/PDFR-1 neuropeptide signaling-dependent pathway. We also demonstrate that genetic variation affects food-dependent larval and adult phenotypes, and identify quantitative trait loci (QTL) associated with these traits. Together, these results suggest that TORC2 acts as a hub for communication of feeding state information from the gut to the brain, thereby contributing to modulation of neuronal function by internal state.动物会将外部线索与代谢状态等内部条件信息加以整合，以做出适配性的行为与发育决策。肠道可感知食物的质量与数量相关信息，并通过尚未完全阐明的机制传递信号以调控神经元功能。保守型雷帕霉素靶蛋白复合物2（Target of Rapamycin complex 2, TORC2）可响应细胞应激因子与生长因子，调控多种生命过程。本研究证实，在食细菌线虫秀丽隐杆线虫（C. elegans）中，TORC2可协调幼虫发育与成虫行为，以响应环境线索与进食状态。发育过程中，信息素、细菌食物与温度可调控感觉神经元中daf-7转化生长因子-β（TGF-β）与daf-28胰岛素样肽的表达，从而在生殖生长与进入替代性dauer滞育幼虫阶段之间做出二元抉择。我们发现，TORC2在肠道中发挥作用，调节daf-7与daf-28的神经元表达，二者的表达水平共同反映了依赖细菌饮食的进食状态，从而为食物信号与外部线索在神经内分泌基因表达调控中的整合提供了机制。在成虫体内，TORC2同样通过肠道作用，经PDF-2/PDFR-1神经肽信号依赖通路调节食物依赖的觅食行为。我们还证实，遗传变异会影响食物依赖的幼虫与成虫表型，并鉴定出与这些性状相关的数量性状位点（QTL）。综上，上述结果表明，TORC2作为将进食状态信息从肠道传递至大脑的枢纽，参与了内部状态对神经元功能的调控。