Clustering of Genetically Defined Allele Classes in the <i>Caenorhabditis elegans</i> DAF-2 Insulin/IGF-1 Receptor

Patel, Dhaval; Garza-Garcia, Acely; Nanji, Manoj; McElwee, Joshua; Ackerman, Daniel; Driscoll, Paul C.; Gems, David

doi:10.1534/genetics.107.070813

Cited by 78 publications

(101 citation statements)

References 84 publications

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“…Because this contradicted the weak anti-apoptotic role previously reported for daf-2 in the worm germline, 12,13 we examined two additional alleles of daf-2 ( Figure 1b) and ablated daf-2 by RNA interference (RNAi) (see below). Even though the e1370, e1391 and m596 alleles affect distinct regions of the daf-2 locus, 14 all three mutations caused strong resistance to apoptosis. We also quantified IR-induced apoptosis in daf-2(e1370) mutants grown at 201C, where only 15% of larva form dauers, and found that resistance to DNA damage was preserved (see Figure 4b) but not at the permissive temperature of 151C (not shown).…”

Section: Resultsmentioning

confidence: 99%

Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways

Perrin

Gunda

et al. 2012

Cell Death Differ

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The insulin/IGF-1 pathway controls a number of physiological processes in the nematode worm Caenorhabditis elegans, including development, aging and stress response. We previously found that the Akt/PKB ortholog AKT-1 dampens the apoptotic response to genotoxic stress in the germline by negatively regulating the p53-like transcription factor CEP-1. Here, we report unexpected rearrangements to the insulin/IGF-1 pathway, whereby the insulin-like receptor DAF-2 and 3-phosphoinositidedependent protein kinase PDK-1 oppose AKT-1 to promote DNA damage-induced apoptosis. While DNA damage does not affect phosphorylation at the PDK-1 site Thr350/Thr308 of AKT-1, it increased phosphorylation at Ser517/Ser473. Although ablation of daf-2 or pdk-1 completely suppressed akt-1-dependent apoptosis, the transcriptional activation of CEP-1 was unaffected, suggesting that daf-2 and pdk-1 act independently or downstream of cep-1 and akt-1. Ablation of the akt-1 paralog akt-2 or the downstream target of the insulin/IGF-1 pathway daf-16 (a FOXO transcription factor) restored sensitivity to damage-induced apoptosis in daf-2 and pdk-1 mutants. In addition, daf-2 and pdk-1 mutants have reduced levels of phospho-MPK-1/ERK in their germ cells, indicating that the insulin/IGF-1 pathway promotes Ras signaling in the germline. Ablation of the Ras effector gla-3, a negative regulator of mpk-1, restored sensitivity to apoptosis in daf-2 mutants, suggesting that gla-3 acts downstream of daf-2. In addition, the hypersensitivity of let-60/Ras gain-of-function mutants to damage-induced apoptosis was suppressed to wild-type levels by ablation of daf-2. Thus, insulin/IGF-1 signaling selectively engages AKT-2/DAF-16 to promote DNA damage-induced germ cell apoptosis downstream of CEP-1 through the Ras pathway.

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Section: Resultsmentioning

confidence: 99%

Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways

Perrin

Gunda

et al. 2012

Cell Death Differ

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“…terminal arrest phenotype. Consistent with this interpretation, the null phenotype of daf-2 includes embryonic lethality (Gems et al 1998;Patel et al 2008). However, daf-2 mutants are temperature sensitive, and Baugh and Sternberg (2006) showed that constitutive L1 arrest of daf-2 (e979) could be reversed at the permissive temperature producing reproductive adults.…”

Section: Daf-2/insrmentioning

confidence: 87%

To Grow or Not to Grow: Nutritional Control of Development DuringCaenorhabditis elegansL1 Arrest

2013

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It is widely appreciated that larvae of the nematode Caenorhabditis elegans arrest development by forming dauer larvae in response to multiple unfavorable environmental conditions. C. elegans larvae can also reversibly arrest development earlier, during the first larval stage (L1), in response to starvation. "L1 arrest" (also known as "L1 diapause") occurs without morphological modification but is accompanied by increased stress resistance. Caloric restriction and periodic fasting can extend adult lifespan, and developmental models are critical to understanding how the animal is buffered from fluctuations in nutrient availability, impacting lifespan. L1 arrest provides an opportunity to study nutritional control of development. Given its relevance to aging, diabetes, obesity and cancer, interest in L1 arrest is increasing, and signaling pathways and gene regulatory mechanisms controlling arrest and recovery have been characterized. Insulin-like signaling is a critical regulator, and it is modified by and acts through microRNAs. DAF-18/PTEN, AMP-activated kinase and fatty acid biosynthesis are also involved. The nervous system, epidermis, and intestine contribute systemically to regulation of arrest, but cell-autonomous signaling likely contributes to regulation in the germline. A relatively small number of genes affecting starvation survival during L1 arrest are known, and many of them also affect adult lifespan, reflecting a common genetic basis ripe for exploration. mRNA expression is well characterized during arrest, recovery, and normal L1 development, providing a metazoan model for nutritional control of gene expression. In particular, post-recruitment regulation of RNA polymerase II is under nutritional control, potentially contributing to a rapid and coordinated response to feeding. The phenomenology of L1 arrest will be reviewed, as well as regulation of developmental arrest and starvation survival by various signaling pathways and gene regulatory mechanisms.

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“…The daf-2(e1368) allele has a mutation in the extracellular domain of the protein and is weaker than the e1370 allele, which has an intracellular mutation (Patel et al 2008). A total of 250 mm glucose stress suppressed dauer formation in both the daf-2 insulin-like receptor alleles ( Figure 6B).…”

Section: ; Mondoux Et Al 2010)mentioning

confidence: 99%

O-Linked-N-Acetylglucosamine Cycling and Insulin Signaling Are Required for the Glucose Stress Response inCaenorhabditis elegans

et al. 2011

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In a variety of organisms, including worms, flies, and mammals, glucose homeostasis is maintained by insulin-like signaling in a robust network of opposing and complementary signaling pathways. The hexosamine signaling pathway, terminating in O-linked-N-acetylglucosamine (O-GlcNAc) cycling, is a key sensor of nutrient status and has been genetically linked to the regulation of insulin signaling in Caenorhabditis elegans. Here we demonstrate that O-GlcNAc cycling and insulin signaling are both essential components of the C. elegans response to glucose stress. A number of insulin-dependent processes were found to be sensitive to glucose stress, including fertility, reproductive timing, and dauer formation, yet each of these differed in their threshold of sensitivity to glucose excess. Our findings suggest that O-GlcNAc cycling and insulin signaling are both required for a robust and adaptable response to glucose stress, but these two pathways show complex and interdependent roles in the maintenance of glucose-insulin homeostasis.

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Clustering of Genetically Defined Allele Classes in the Caenorhabditis elegans DAF-2 Insulin/IGF-1 Receptor

Cited by 78 publications

References 84 publications

Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways

Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways

To Grow or Not to Grow: Nutritional Control of Development DuringCaenorhabditis elegansL1 Arrest

O-Linked-N-Acetylglucosamine Cycling and Insulin Signaling Are Required for the Glucose Stress Response inCaenorhabditis elegans

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