C. elegans VANG-1 Modulates Life Span via Insulin/IGF-1-Like Signaling

Sebastian J Honnen,Andreas Kampkötter,Verena Schröder,Olaf Bossinger,Michael Hoffmann,Yuji Kohara,Christian Büchter,Anne C Hart

doi:10.1371/journal.pone.0032183

Abstract

The planar cell polarity (PCP) pathway is highly conserved from Drosophila to humans and a PCP-like pathway has recently been described in the nematode Caenorhabditis elegans. The developmental function of this pathway is to coordinate the orientation of cells or structures within the plane of an epithelium or to organize cell-cell intercalation required for correct morphogenesis. Here, we describe a novel role of VANG-1, the only C. elegans ortholog of the conserved PCP component Strabismus/Van Gogh. We show that two alleles of vang-1 and depletion of the protein by RNAi cause an increase of mean life span up to 40%. Consistent with the longevity phenotype vang-1 animals also show enhanced resistance to thermal- and oxidative stress and decreased lipofuscin accumulation. In addition, vang-1 mutants show defects like reduced brood size, decreased ovulation rate and prolonged reproductive span, which are also related to gerontogenes. The germline, but not the intestine or neurons, seems to be the primary site of vang-1 function. Life span extension in vang-1 mutants depends on the insulin/IGF-1-like receptor DAF-2 and DAF-16/FoxO transcription factor. RNAi against the phase II detoxification transcription factor SKN-1/Nrf2 also reduced vang-1 life span that might be explained by gradual inhibition of insulin/IGF-1-like signaling in vang-1. This is the first time that a key player of the PCP pathway is shown to be involved in the insulin/IGF-1-like signaling dependent modulation of life span in C. elegans.

Highlights

Wnt/planar cell polarity (PCP) is one of three identified Wnt signaling pathways, along with Wnt/ß–Catenin and Wnt/ Calcium [1]
The C. elegans genome encodes a sole four-pass transmembrane protein, VANG-1 showing sequence similarities and conservation of overall domain architecture compared to the Strabismus/Van Gogh/Ltap proteins identified in Drosophila, Xenopus and mammals
Results and Discussion vang-1 increases life span, stress resistance and reproductive span in C. elegans The C. elegans genome contains a sole four-pass transmembrane protein with homology to the Strabismus/Van Gogh/Ltap proteins identified in Drosophila, Xenopus and mammals [32,33,34]

Summary

Introduction

Wnt/planar cell polarity (PCP) is one of three identified Wnt signaling pathways, along with Wnt/ß–Catenin and Wnt/ Calcium [1]. We identify VANG-1, the only C. elegans ortholog of the conserved PCP protein Strabismus/Van Gogh, as a gerontogene with a typical phenotype, including extended lifeand reproductive span, multiple stress resistances, slow growth, reduced brood size and reduced lipofuscin accumulation. We noticed a significant extension of C. elegans mean life span up to 27% and 20% in comparison to WT controls either kept on standard OP50 or RNAi HT115 bacteria with the empty ‘‘feeding’’-vector.

Results

Conclusion