| | | [C.elegansII] e1370ts : constitutive dauer formation at 25C; reversible by shift to 15C. Increased lifespanat 20C; increased thermotolerance, UV resistance. Non-Srf. Synthetic lethal with daf-12. ES3 (L3). OA>40: e1032, e1286, e1365, sa230 (100%Daf-c at all temperatures), sa223 (sterile), m65 (nonconditional), etc. Most alleles (not e1370) hypersensitive to dauer pheromone. [Larsen et al. 1995; Malone and Thomas 1994; CF; JC] |
| | Structured_description | Concise_description | daf-2 encodes a receptor tyrosine kinase that is the C. elegans insulin/IGF receptor ortholog; DAF-2 activity is required for a number of processes in C. elegans, including embryonic and larval development, formation of the developmentally arrested dauer larval stage (diapause), larval developmental timing, adult longevity, reproduction, fat storage, salt chemotaxis learning, and stress resistance, including response to high temperature, oxidative stress, and bacterial infection; DAF-2 signals through a conserved PI 3-kinase pathway to negatively regulate the activity of DAF-16, a Forkhead-related transcription factor, by inducing its phosphorylation and nuclear exclusion; in addition, DAF-2 negatively regulates the nuclear localization, and hence transcriptional activity, of SKN-1 in intestinal nuclei; amongst the 38 predicted insulin-like molecules in C. elegans, genetic and microarray analyses suggest that at least DAF-28, INS-1, and INS-7 are likely DAF-2 ligands; genetic mosaic and tissue-specific promoter studies indicate that daf-2 can function cell nonautonomously and within multiple cell types to influence dauer formation and adult lifespan, likely by regulating the production of secondary endocrine signals that coordinate growth and longevity throughout the animal; temporal analysis of daf-2 function indicates that daf-2 regulates lifespan, reproduction, and diapause independently, at distinct times during the animal's life cycle. | Paper_evidence (11) |
| | Disease_relevance | Parkinson''s disease (PD) is an age-dependent neurodegenerative disease characterized by the accumulation of alpha-synuclein (alpha-syn) and the selective loss of dopamine (DA) neurons; studies in C. elegans models of alpha-syn proteotoxcity indicate that reduced IGF-1/insulin-like signaling (IIS) suppresses alpha-syn toxicity and DA neurodegeneration; specifically daf-2 mutant worms that overexpress human alpha-syn retain more wild-type DA neurons when compared to alpha-syn worms alone; mutants of daf-16/FOXO, a well-characterized downstream component of the IIS pathway enhanced neurodegeneration, and an intermediate level of neuroprotection was seen in daf-2; daf-16 double mutants overexpressing alpha-syn-GFP in DA neurons; further, RNA interference of glucose-6-phosphate isomerase (gpi-1/GPI), the glycolytic enzyme, enhanced alpha-syn-induced DA neurotoxicity, while it''s overexpression in DA neurons was neuroprotective; further studies in Drosophila and mice confirm that GPI is neuroprotective; these studies indicate that IIS signaling modulates alpha-syn induced DA neurodegeneration, across species. | Homo sapiens | Paper_evidence (3) |