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Parallel pathways for serotonin biosynthesis and metabolism in C. elegans

A Publisher Correction to this article was published on 18 November 2022

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Abstract

The neurotransmitter serotonin plays a central role in animal behavior and physiology, and many of its functions are regulated via evolutionarily conserved biosynthesis and degradation pathways. Here we show that in Caenorhabditis elegans, serotonin is abundantly produced in nonneuronal tissues via phenylalanine hydroxylase, in addition to canonical biosynthesis via tryptophan hydroxylase in neurons. Combining CRISPR–Cas9 genome editing, comparative metabolomics and synthesis, we demonstrate that most serotonin in C. elegans is incorporated into N-acetylserotonin-derived glucosides, which are retained in the worm body and further modified via the carboxylesterase CEST-4. Expression patterns of CEST-4 suggest that serotonin or serotonin derivatives are transported between different tissues. Last, we show that bacterial indole production interacts with serotonin metabolism via CEST-4. Our results reveal a parallel pathway for serotonin biosynthesis in nonneuronal cell types and further indicate that serotonin-derived metabolites may serve distinct signaling functions and contribute to previously described serotonin-dependent phenotypes.

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Fig. 1: Monoamine neurotransmitter biosynthesis and serotonin supplementation.
Fig. 2: Identification of serotonin-derived MOGLs.
Fig. 3: PAH-1 contributes to serotonin biosynthesis.
Fig. 4: PAH-1 contributes to serotonin-related behaviors.
Fig. 5: Biosynthesis model for serotonin-derived metabolites.

Data availability

Source data are provided with this paper. The HPLC–HRMS and MS/MS data generated during this study have been deposited at MassIVE (gnps.ucsd.edu) under accession code MSV000088750 (https://doi.org/10.25345/C55W01). Source data are provided with this paper.

Code availability

Metaboseek is available as an R package, with installation instructions for Windows, macOS, and Linux. A preconfigured R-portable installation is available as installer or.zip file for Windows. Source code, documentation and a tutorial vignette are available at https://github.com/mjhelf/Metaboseek and https://doi.org/10.5281/zenodo.3360087. Individual functions for spectra comparison, merging spectra and filtering molecular formulae have been moved to the companion R package MassTools, with source code and documentation available at https://github.com/mjhelf/MassTools and https://doi.org/10.5281/zenodo.5725620. The Metaboseek tutorial is also available at https://metaboseek.com/doc.

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Acknowledgements

This research was supported in part by the National Institutes of Health (grant nos. R35GM131877 to F.C.S. and T32GM008500 to B.J.C.) and the Howard Hughes Medical Institute. Some strains used in this work were provided by the CGC, which is funded by the National Institutes of Health Office of Research Infrastructure Programs (grant no. P40 OD010440). We thank G. Horvath for technical support and D. Kiemle for assistance with NMR spectroscopy.

Author information

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Authors

Contributions

F.C.S., J.Y. and M.C.V. conceived the experimental design. F.C.S. and O.H. supervised the study. J.Y., B.W.F., C.J.J.W., B.Z. and H.H.L. performed HPLC–MS analyses and comparative metabolomics, D.F.P. assisted with providing worm strains and biological experiments. M.C.V., J.Y. and D.F.P. performed bioassays with serotonin and derivatives, A.T. contributed data for different life stages and starvation conditions, J.Y. and B.J.C. performed chemical synthesis. J.Y., M.C.V., O.H. and F.C.S. wrote the paper with input from all authors.

Corresponding authors

Correspondence to Oliver Hobert or Frank C. Schroeder.

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The authors declare no competing interests.

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Nature Chemical Biology thanks Riekelt Houtkooper, Yue Zhou and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Metabolic changes with 5 mM serotonin treatment in C. elegans.

a, ESI+ ion chromatograms for melatonin synthetic standard and WT C. elegans endo-metabolome extracts. Melatonin was only detected in WT treated with an unphysiologically high concentration (5 mM) of serotonin but was not detected in untreated WT animals. b, Relative abundances of known serotonin metabolites in exo- and endo-metabolome samples of WT treated with 5 mM serotonin. c, Abundances of N-acyl-glycoglycerophosphoethanolamines (GLEAs) in endo-metabolomes of WT treated with 5 mM serotonin. 15 ≤ m ≤ 19, 26 ≤ n ≤ 30, x = 0 or 1. d, Structures of indole-derived MOGLs whose abundances were decreased in WT treated with 5 mM serotonin. Data in b and c represent 3 biologically independent experiments and bars indicate mean ± s.d., p-values calculated via unpaired, two-tailed t-test with Welch correction.

Source data

Extended Data Fig. 2 Identification of serotonin-derived glucosides.

a, ESI+ ion chromatograms for sngl#1 in WT, synthetic standards, and for co-injections of natural and synthetic samples. b, ESI+ ion chromatograms for sngl#1 (HILIC column) in endo-metabolome of WT and synthetic standard. c, ESI+ ion chromatograms for sngl#101, sngl#1 and 36 in WT and synthetic standards, indicating that the β-O-linked serotonin glucoside (sngl#1) was the by far major isomer, compared to α-O-linked 36. d, ESI+ ion chromatogram for sngl#101 in WT and synthetic standard. Y-axis for m/z 403.1476 was scaled 10-fold relative to chromatogram shown in panel c to highlight presence of trace amounts of sngl#101. e, Abundance of β-N- linked sngl#101 relative to β-O-linked sngl#1 in WT. f, Abundances of sngl#101 and sngl#1 in WT treated with 5 mM serotonin. g, h, ESI ion chromatograms for sngl#2 (g) and sngl#4 (h) in endo-metabolomes of WT and synthetic standards using a C18 column. i-k, Chromatograms for sngl#2 (Amide HILIC column, ESI), sngl#3 (HILIC column, ESI+) and sngl#4 (Amide HILIC column, ESI) in endo-metabolomes of WT and synthetic standards. l, ESI+ MS/MS spectrum and proposed fragmentation of sngl#6. m, Relative abundance of serotonin derived metabolites in endo- and exo-metabolomes of unsupplemented WT. Data in e (n = 18), f (n = 3) and m (n = 3) represent biologically independent experiments and bars indicate mean ± s.d., p-values calculated by unpaired, two-tailed t-test with Welch correction.

Source data

Extended Data Fig. 3 Metabolomic analysis of serotonin biosynthesis mutants.

a, sngl#4 biosynthesis was abolished in pah-1(syb3596);tph-1(mg280) and bas-1(ad446) but not tph-1(mg280) or pah-1(syb3601) mutants. b, Abundances of serotonin derivatives in two tph-1 alleles, tph-1(mg280) and tph-1(n4622), grown in parallel replicates. c, Relative abundances of serotonin derivatives in tph-1(n4622) endo-metabolome samples. d, Relative abundances of serotonin derivatives in cat-2(e1112) endo-metabolome samples. e, Scheme for quantitation of free serotonin via derivatization. f, g, Relative abundances of neurotransmitters dopamine (f) and tyramine (g) in WT, tph-1(mg280), tph-1(n4622), pah-1(syb3601), and pah-1(syb3596);tph-1(mg280) endo-metabolomes. Data in b (n = 3), c (n = 6), f and g (tph-1(mg280): n = 8, tph-1(n4622): n = 8, pah-1(syb3601): n = 7, pah-1(syb3596);tph-1(mg280): n = 4, bas-1(ad446): n = 4) represent biologically independent experiments and bars indicate mean ± s.d., p-values calculated via unpaired, two-tailed t-test with Welch correction, comparing mutant animals and WT. h, ESI+ ion chromatograms for m/z 221.0920 for bas-1(ad446) mutant, pah-1(syb3596);tph-1(mg280) double mutant, and WT endo-metabolomes as well as a 2 μM 5-HTP synthetic standard and co-injection with WT endo-metabolome. i, Enlargement of ESI+ ion chromatograms for m/z 221.0920 for bas-1(ad446), pah-1(syb3596);tph-1(mg280) double mutant, and WT endo-metabolomes as well as 50 nM synthetic standard of 5-HTP. Neither of the shown endo-metabolome chromatograms shows a significant peak for 5-HTP.

Source data

Extended Data Fig. 4 Serotonin-related behaviors of different mutants.

a, Heat map of locomotory behaviors of pah-1(syb3601), tph-1(mg280), pah-1(syb3596);tph-1(mg280) compared to WT. Fed day-1 adult animals were tracked using an automated single worm tracker. pah-1(syb3601) mutant animals (n = 46) did not show any gross defects in locomotion compared to WT. Features significantly different (q-value(Wilcoxon) <0.05) between WT (n = 42) and tph-1(mg280) (n = 40) mutant animals are displayed as fold change in relation to WT (red: upregulated compared to WT; blue: downregulated compared to WT). Except for foraging, pah-1(syb3596);tph-1(mg280) double mutants (n = 47) display significant changes in the same locomotory features compared to WT as observed between WT and tph-1(mg280) animals. n.s., not significant. b, Loss of PAH-1 did not result in gross locomotory defects. Fed day 1 adult animals were tracked using an automated single worm tracker. pah-1(syb3601) mutant animals did not show any gross defects in locomotion compared to WT. Features significantly different (q-value (Wilcoxon) <0.05) between WT and tph-1(mg280) mutant animals are displayed as boxplots with individual values for each animal tested. Additional loss of PAH-1 does not exacerbate phenotypes observed in tph-1(mg280) single mutants. Boxplots were generated using Worm Tracker (v2.0). Red center line indicates mean with 95 % confidence intervals (white box), outer boxes indicate standard deviation. c, Loss of PAH-1 significantly increased exploratory behavior after 6 h, to a larger extent than loss of TPH-1. d, Exogenous NAS did not influence exploratory behavior of WT after 13.5 h. Data in c (n = 20 per experiment per genotype and treatment) were collected in 2 biologically independent experiments. Data in d (n = 10 and n = 11 for the first two experiments and n = 12 for the third experiment) were collected in 3 biologically independent. Statistics in b-d were calculated using One-Way-ANOVA and p-values were adjusted with posthoc Tukey’s multiple comparison test. n.s., not significant.

Source data

Extended Data Fig. 5 Life stage, starvation, and microbial metabolism affect serotonin metabolite biosynthesis.

a, Abundances of sngl#1–4 in exo-metabolomes of glo-1 mutants relative to WT. b, Abundances of sngl#1-4 in cest mutants (cest-4, cest-1.1, cest-1.2, cest-2.2, cest-3, cest-5.1, cest-5.2, cest-6, cest-7, cest-8, cest-9.1, cest-19, cest-33, ges-1) relative to WT. n.d., not detected. c, Absolute concentrations of NAS, sngl#1, sngl#2, sngl#3, and sngl#4 in WT C. elegans at day 7 of adulthood. d, Abundances of sngl#1-4 in the endo-metabolomes of WT C. elegans at day 1, day 5, and day 7 of adulthood. e, ESI+ and ESI ion chromatograms for NAS and sngl#1-4 in endo-metabolomes of E. coli OP50 and WT C. elegans, demonstrating that NAS and serotonin glucosides sngl#1-4 are not produced by OP50. f, Abundances of free indole and iglu#-family metabolites in endo-metabolome samples of WT C. elegans fed BW25113 or ΔtnaA E. coli bacteria. Data in a (n = 3), b (n = 2-4), c (n = 3), d (n = 3), and f (n = 7) represent biologically independent experiments, and bars indicate mean ± s.d., p-values calculated by unpaired, two-tailed t-test with Welch correction; n.s., not significant.

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Yu, J., Vogt, M.C., Fox, B.W. et al. Parallel pathways for serotonin biosynthesis and metabolism in C. elegans. Nat Chem Biol 19, 141–150 (2023). https://doi.org/10.1038/s41589-022-01148-7

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