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Communicated by Gregory A. Petsko, Brandeis University, Waltham, MA (received for review February 9, 1999)
Article Figures & SI
Figures
- Figure 1
CePTEN/daf-18 gene structure. (A) Genomic structure. The exons are depicted as black boxes and numbered. The nr2037 allele contains a deletion that covers part of intron II and exon III. The phosphatase catalytic center, HCKAGKGRTG, abbreviated as the HC motif (double underlined), is deleted in the nr2037 mutant. The ΔBspHI deletion construct, in which exon I and II of the CePTEN/daf-18 gene is removed, is used as a control for the genomic rescue experiment (see Table 1). The 30-bp insertion found in the daf-18(e1375) allele is located in exon IV in the noncatalytic domain of CePTEN/DAF-18. This insertion occurs after codon 574, leading to a frameshift and premature stop codon. (B) Amino acid alignment of the amino-terminal phosphatase domain of CePTEN/DAF-18 and human PTEN. The phosphatase catalytic center, HCKAGKGRTG, is double underlined. Identical residues are shown as white letters in black boxes.
- Figure 2
Morphological comparison of daf-18, daf-2, and daf-2; daf-18 strains. (Left) Nomarski micrographs. The head of the animal is shown. The two bulbs of the pharynx are indicated by the arrowheads. (Right) Brightfield micrographs. Transgenic animals, shown in the Bottom two rows, carry an extrachromosomal array of either the functional daf-18 gene (Ex[daf-18(+)]), or a mutant derivative that removes exons I and II (Ex[daf-18(−)]). The animals with genotypes daf-2(e1370) and daf-2(e1370); daf-18(nr2037); Ex[daf-18(+)] are dauer larvae and appear thinner in the brightfield micrographs and have a constricted pharynx as shown in the Nomarski micrographs. Wild-type animals and animals with genotypes daf-18(nr2037), daf-2(e1370); daf-18(nr2037) and daf-2(e1370); daf-18(nr2037); Ex[daf-18(-)] are non-dauer L3 larvae.
- Figure 3
Effects of the daf-18(nr2037) mutation on adult lifespans. (A) Lifespans at 25°C. (B) Lifespans at 20°C. The percentage of live animals was plotted as a function of time (days). Wild-type (Bristol N2), daf-18(nr2037), daf-2(e1370), and daf-2(e1370); daf-18(nr2037) strains were compared in parallel. Representatives of two independent sets of experiments are shown. The results were similar in both sets of experiments.
- Figure 4
Model for DAF-18 action. AGE-1 is the major signal transducer for the activated DAF-2 insulin receptor-like molecule in regulation of dauer development and lifespan. AGE-1 is predicted to produce PIP3, which negatively regulates lifespan and dauer-formation processes. DAF-18, the PTEN homolog, functions to dephosphorylate PIP3 and thus antagonizes the action of DAF-2 and AGE-1. DAF-18 may also be negatively regulated by DAF-2 (dashed line).
Tables
- Table 1
The daf-18(nr2037) mutation suppresses the dauer-constitutive phenotype of daf-2(e1370)
Genotype of parent Transgene Phenotype of progeny at 25°C, % L4 and adult Dauer Partial dauer Other n Wild type none 100 0 0 0 250 daf-2(e1370) none 0 100 0 0 376 daf-18(nr2037) none 98.5 0 0 1.5 200 daf-2(e1370); daf-18(nr2037) none 96.5 0 0 3.5 310 daf-2(e1370); daf-18(nr2037) daf-18(+) 0 93.5 4.3 2.2 203 daf-2(e1370); daf-18(nr2037) daf-18(−) 99 0 0 1.0 205 -
Eggs were collected at 20°C during a 10-hour period and then shifted to 25°C. Phenotypes were scored at 48 hours after the temperature shift and confirmed by rescoring 24 hours later. Partial dauers are defined as those with less constriction or with less darkness of the intestine than typical dauer progeny observed in the daf-2(e1370) strain. “Other” includes animals that died as young larvae or those with grossly abnormal morphology. Wild type, Bristol N2 strain. n, total number of animals scored.
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Stable transgenic lines were established using the wild-type genomic daf-18 fragment, daf-18(+), or the same fragment with a deletion of exons 1 and 2, daf-18(−). Transgene data are the combined total from three independent lines.
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- Table 2
The daf-18(nr2037) mutation suppresses the dauer-constitutive phenotype of age-1(m333)
Genotype of parent Phenotype of Progeny at 20°C, % L4 and adult Dauer Partial dauer Others n age-1(m333) 0 100 0 0 410 age-1(m333); daf-18(nr2037) 100 0 0 0 320 -
Eggs were collected at 20°C during a 10-hour period and maintained at 20°C. Phenotypes were scored twice, first at 48 hours, and then again at 72 hours after egg laying. Homozygous age-1(m333)/age-1(m333) hermaphrodites were obtained from age-1(m333)/mnC1[dpy-10(e128) unc-52(e444)] parents. Definitions for the partial dauers or others are as in Table 1. n, total number of animals scored.
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Strain Lifespan, days Mean (±SE) Ratio vs. wildtype Maximum n 25°C* Wild type 8.5 (±0.3) 1.0 14 34 daf-18(nr2037) 6.2 (±0.2) 0.7 9 48 daf-2(e1370) 18.8 (±0.5) 2.2 31 49 daf-2(e1370); daf-18(nr2037) 8.3 (±0.4) 1.0 18 49 20°C† Wild type 12.7 (±0.3) 1.0 22 50 daf-18(nr2037) 5.8 (±0.5) 0.5 15 42 daf-2(e1370) 25.3 (±0.5) 2.0 42 50 daf-2(e1370); daf-18(nr2037) 11.1 (±0.5) 0.9 21 50 -
Values are calculated using the data from the experiments shown in Fig. 3. The relative ratio of the mean over that of the wild-type (Bristol N2) strain is also shown. All experiments were performed at least two times with similar results obtained. n, total number of animals scored.
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↵* The animals were raised at 15°C until the L4 or adult stage and then shifted to 25°C. The day of the shift is counted as day 0 in the adult lifespan assay.
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↵† The animals were raised and maintained at 20°C. Young adults or L4s were transferred to new plates to assay for lifespan. The day of the transfer is counted as day 0 in the adult lifespan assay.
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The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway
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