Originally published as Genetics Published Articles Ahead of Print on August 24, 2007.

Genetics, Vol. 177, 835-845, October 2007, Copyright © 2007
doi:10.1534/genetics.107.076901

Gravity Force Transduced by the MEC-4/MEC-10 DEG/ENaC Channel Modulates DAF-16/FoxO Activity in Caenorhabditis elegans

Nahui Kim^*,, Catherine M. Dempsey^,2, Chih-Jen Kuan, Jim V. Zoval, Eyleen O'Rourke, Gary Ruvkun, Marc J. Madou and Ji Y. Sze^,1

^* Interdisciplinary Materials Science and Engineering, Department of Mechanical and Aerospace Engineering, University of California, Irvine, California 92697, Department of Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York 10461 and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114

¹ Corresponding author: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University, 202 Golding Building, 1300 Morris Park Avenue, Bronx, NY 10461.
E-mail: jsze{at}aecom.yu.edu

The gravity response is an array of behavioral and physiological plasticity elicited by changes in ambient mechanical force and is an evolutionarily ancient adaptive mechanism. We show in Caenorhabditis elegans that the force of hypergravity is translated into biological signaling via a genetic pathway involving three factors: the degenerin/epithelial Na⁺ channel (DEG/ENaC) class of mechanosensory channels of touch receptor neurons, the neurotransmitter serotonin, and the FoxO transcription factor DAF-16 known to regulate development, energy metabolism, stress responses, and aging. After worms were exposed to hypergravity for 3 hr, their muscular and neuronal functions were preserved, but they exhibited DAF-16::GFP nuclear accumulation in cells throughout the body and accumulated excess fat. Mutations in MEC-4/MEC-10 DEG/ENaC or its partners MEC-6, MEC-7, and MEC-9 blocked DAF-16::GFP nuclear accumulation induced by hypergravity but did not affect DAF-16 response to other stresses. We show that exogenous serotonin and the antidepressant fluoxetine can attenuate DAF-16::GFP nuclear accumulation in WT animals exposed to hypergravity. These results reveal a novel physiological role of the mechanosensory channel, showing that the perception of mechanical stress controls FoxO signaling pathways and that inactivation of DEG/ENaC may decouple mechanical loading and physiological responses.

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