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

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.

Run-on of germline apoptosis promotes gonad senescence inC. elegans

“…We present evidence that post-reproductive physiological apoptosis promotes germline atrophy (Figure 6B), and also that run-on of endomitosis promotes hypertrophy in un-ovulated oocytes. The latter is consistent with previous evidence that endomitosis contributes to development of tumors from unfertilized oocytes in the uterus [19]. Moreover, post-reproductive hermaphrodites accumulate large quantities of yolk in the body cavity, as the result of run-on of intestinal yolk synthesis [48, 49] (Figure 6B).…”

“…Uterine tumor formation appears to result from run-on of growth in unfertilized oocytes [16–19]. We explored the possibility that distal gonad disintegration also results from run-on of functions that promote early life fitness.…”

“…Several studies suggest not: for example, lifespan was not extended either by blocking uterine tumor growth [19] or blocking apoptosis using ced-3(n1286) [20]. However, several studies have reported increases in lifespan resulting from loss of ced-3 function, either using ced-3(n717) [31], like ced-3(n1286) a strong allele [32], or ced-3 RNAi initiated at L4 [33], which suppresses only germline apoptosis.…”

“…Initially, after depletion of sperm, unfertilized oocytes accumulate [16] and enter the uterus, where they become hypertrophic, forming large tumors [17–19]. By contrast, the aging distal gonad undergoes severe atrophy and eventual disintegration [16, 18, 20].…”

MicroRNA mir-34 provides robustness to environmental stress response via the DAF-16 network in C. elegans

“…mdl-1 is a basic helix-loop-helix (bHLH) transcription factor that acts as a part of the Myc-like interaction network in C. elegans. S imilar to vertebrate MAD, MDL-1 dimerizes with MXL-1 and MXL-3 and plays a role in integrating diverse longevity signals464748. The mdl-1 gene promoter is bound by DAF-16 and PQM-1, according to modENCODE data35, and the mdl-1 mRNA is targeted by miR-34 according to AGO-CLIP data39 and MIRZA prediction, although the MIRZA score is modest (Table S1).…”