MDL-1, a growth- and tumor-suppressor, slows aging and prevents germline hyperplasia and hypertrophy in C. elegans

Michèle Riesen,Ann F Gilliat,Jennifer M.A Tullet,Inna Feyst,Marina Ezcurra,David Gems,Matthias Ziehm,Josephine Hellberg,Catherine Au,Janet M Thornton,Nattaphong Rattanavirotkul,Irene Papatheodorou

doi:10.18632/aging.100638

Michèle Riesen, Ann F Gilliat + Show 10 more

Open Access

https://doi.org/10.18632/aging.100638

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Abstract

In C. elegans, increased lifespan in daf-2 insulin/IGF-1 receptor mutants is accompanied by up-regulation of the MDL-1 Mad basic helix-loop-helix leucine zipper transcription factor. Here we describe the role of mdl-1 in C. elegans germline proliferation and aging. The deletion allele mdl-1(tm311) shortened lifespan, and did so significantly more so in long-lived daf-2 mutants implying that mdl-1(+) contributes to effects of daf-2 on lifespan. mdl-1 mutant hermaphrodites also lay increased numbers of unfertilized oocytes. During aging, unfertilized oocytes in the uterus develop into tumors, whose development was accelerated by mdl-1(tm311). Opposite phenotypes were seen in daf-2 mutants, i.e. mdl-1 and daf-2 mutant germlines are hyperplastic and hypoplastic, respectively. Thus, MDL-1, like its mammalian orthologs, is an inhibitor of cell proliferation and growth that slows progression of an age-related pathology in C. elegans (uterine tumors). In addition, intestine-limited rescue of mdl-1 increased lifespan but not to wild type levels. Thus, mdl-1 likely acts both in the intestine and the germline to influence age-related mortality.

Highlights

In most animals, advancing age is accompanied by the deteriorative process of aging
We report that mdl-1 acts as a repressor of germline hyperplasia and hypertrophy which otherwise contributes to age-related pathology in the germline
We examined the effect of mdl-1 on lifespan in the absence of uterine tumors. glp-4(bn2) mutants have a temperature-sensitive germline proliferation defect; if raised at 15 ̊C to L4 and switched to 25 ̊C, oocyte production is blocked but longevity is not increased [7]

Summary

INTRODUCTION

In most animals, advancing age is accompanied by the deteriorative process of aging (senescence). Mutation of the daf-2 insulin/IGF-1 receptor gene can more than double adult lifespan [2] This increase requires the presence of the DAF-16 FoxO transcription factor [2,3,4], suggesting that transcriptional targets of DAF-16 encode proximal biochemical determinants of aging. We used a genome-wide approach to identify genes to which DAF-16 both binds and causes a change in gene expression [9] This identified a mere 65 high confidence DAF-16 direct targets, which were enriched for genes encoding proteins involved in signaling and gene regulation, and transcription factors. Mad/Max dimers mainly inhibit gene expression, antagonizing Myc/Max, and suppressing cell division and growth [11]. We report that mdl-1 acts as a repressor of germline hyperplasia and hypertrophy which otherwise contributes to age-related pathology in the germline

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EXPERIMENTAL PROCEDURES