Hypoxia and the HIF-1 transcriptional pathway reorganize a neuronal circuit for oxygen-dependent behavior in Caenorhabditis elegans - PubMed (original) (raw)
Hypoxia and the HIF-1 transcriptional pathway reorganize a neuronal circuit for oxygen-dependent behavior in Caenorhabditis elegans
Andy J Chang et al. Proc Natl Acad Sci U S A. 2008.
Abstract
Rapid behavioral responses to oxygen are generated by specialized sensory neurons that sense hypoxia and hyperoxia. On a slower time scale, many cells respond to oxygen through the activity of the hypoxia-inducible transcription factor HIF-1. Here, we show that in the nematode Caenorhabditis elegans, prolonged growth in hypoxia alters the neuronal circuit for oxygen preference by activating the hif-1 pathway. Activation of hif-1 by hypoxia or by mutations in its negative regulator egl-9/prolyl hydroxylase shifts behavioral oxygen preferences to lower concentrations and eliminates a regulatory input from food. At a neuronal level, hif-1 activation transforms a distributed, regulated neuronal network for oxygen preference into a smaller, fixed network that is constitutively active. The hif-1 pathway acts both in neurons and in gonadal endocrine cells to regulate oxygen preference. These results suggest that physiological detection of hypoxia by multiple tissues provides adaptive information to neuronal circuits to modify behavior.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
Fig. 1.
Cultivation in hypoxia modifies oxygen preference through the egl-9/hif-1 pathway. (A) Diagram showing typical distribution of C. elegans (dots) in an aerotaxis assay. Preferred area is shaded. (B–H) Aerotaxis of wild-type animals and egl-9/hif-1 pathway mutants grown in normoxia or in 1% O2 for 2 days as adults. Asterisks denote distributions different at P < 0.01 by χ2 analysis. (I) The hyperoxia avoidance index, defined as [avg(fraction in 5–14% O2) − avg(fraction in 14–21% O2)]/[avg(fraction in 5–14% O2) + avg(fraction in 14–21% O2)]. Asterisks indicate values different from the same genotype and condition without food at P < 0.05 by t test. Crosses indicate values different from normoxia-grown wild-type on food at P < 0.01 by Dunnett test. In all panels, n ≥ 3 assays per genotype, 80–100 animals/assay; error bars denote standard error of mean (SEM).
Fig. 2.
egl-9/PHD activity in neurons and nonneuronal secretory cells regulates hyperoxia avoidance on food. (A) Expression patterns of egl-9 transgenes under the listed promoters and rescue of aerotaxis and egg-laying. Colored boxes indicate expression of the transgene or rescue of behavior. (See also
SI Methods
.) (B) Hyperoxia avoidance index. ND, not determined. Asterisks indicate values different from the same genotype without food at P < 0.05 by t test. Crosses indicate rescued lines with values different from egl-9 in the presence of food at P < 0.01 by Dunnett test. Aerotaxis assays shown in
Fig. S2
.
Fig. 3.
Induction of the egl-9/hif-1 pathway alters neuronal requirements for hyperoxia avoidance. (A) A distributed network of sensory neurons generates hyperoxia avoidance in wild-type N2 animals (6). URX, AQR, and PQR neurons (URX set) and SDQ, ALN, and BDU neurons (SDQ set) express sGC homologs and are likely oxygen sensors. ASH and ADF neurons express the TRPV channels osm-9 and ocr-2; ADF produces serotonin. In the presence of food, hyperoxia avoidance is suppressed by the activity of the neuropeptide receptor NPR-1 and TGF-β homolog DAF-7. (B) Summary of results in C–H. Aerotaxis of egl-9/PHD mutants requires URX, AQR, and PQR sensory neurons but not TRPV channel-expressing neurons. The NSM neurons are a more important source of serotonin than ADF neurons. (C and D) Effects of qaIs2241 and osm-9 on egl-9 aerotaxis off food. The qaIs2241 transgene kills URX, AQR, and PQR neurons (6). Asterisks denote distributions different from the double mutant at P < 0.01 by χ2 analysis. (E) Hyperoxia avoidance index off food. Asterisks indicate double mutants different from egl-9 controls at P < 0.01 by Dunnett test. Double crosses indicate values different from the designated single mutant at p < 0.05 by Bonferroni t test. Data for some single mutants from ref. . (F and G) Effects of tph-1 on egl-9 aerotaxis off food and rescue of tph-1. ADF promoter was srh-142; NSM promoter was ceh-2; and serotonergic neurons other than ADF and NSM were not tested. Asterisks denote distributions different from tph-1; egl-9 at P < 0.01 by χ2 analysis. (H) Hyperoxia avoidance of tph-1 strains. Asterisks indicate values different from egl-9 control at P < 0.01 by Dunnett test. Crosses and double-crosses indicate values different from nonrescued strain at P < 0.05 by Bonferroni t test. Additional aerotaxis assays shown in
Fig. S3
.
Fig. 4.
Cultivation in hypoxia alters the neural circuit for oxygen preference. (A and B) Aerotaxis of qaIs2241 (URX, AQR, and PQR killed) (A) and osm-9 (B) animals grown in 1% O2 for 2 days as adults. Asterisks denote distributions different at P < 0.01 by χ2 analysis. (C) Hyperoxia avoidance index. Asterisks indicate values different from qaIs2241 at P < 0.05 by Bonferroni t test. Crosses indicate values different from osm-9 at P < 0.05 by Bonferroni t test.
Fig. 5.
egl-9/hif-1, npr-1, and daf-7/TGF-β pathways act independently to modulate oxygen preference. (A, B, and D) Hyperoxia avoidance index and food regulation in egl-9/sensory mutants (A), egl-9/npr-1 mutants (B), and egl-9/daf-7 pathway mutants (D). Asterisks indicate values different from the same genotype without food at P < 0.05 by t test. Some data published in ref. are included for clarity. (C) Aerotaxis of egl-9;npr-1 double mutants. Asterisks indicate distributions different from double mutants at P < 0.01 by χ2 analysis. Additional aerotaxis assays shown in
Fig. S4
.
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