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FMRFamide-like peptides expand the behavioral repertoire of a densely connected nervous system

Lee, James Siho and Shih, Pei-Yin and Schaedel, Oren N. and Quintero-Cadena, Porfirio and Rogers, Alicia K. and Sternberg, Paul W. (2017) FMRFamide-like peptides expand the behavioral repertoire of a densely connected nervous system. Proceedings of the National Academy of Sciences of the United States of America, 114 (50). E10726-E10735. ISSN 0027-8424. PMCID PMC5740649. doi:10.1073/pnas.1710374114.

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Animals, including humans, can adapt to environmental stress through phenotypic plasticity. The free-living nematode Caenorhabditis elegans can adapt to harsh environments by undergoing a whole-animal change, involving exiting reproductive development and entering the stress-resistant dauer larval stage. The dauer is a dispersal stage with dauer-specific behaviors for finding and stowing onto carrier animals, but how dauers acquire these behaviors, despite having a physically limited nervous system of 302 neurons, is poorly understood. We compared dauer and reproductive development using whole-animal RNA sequencing at fine time points and at sufficient depth to measure transcriptional changes within single cells. We detected 8,042 genes differentially expressed during dauer and reproductive development and observed striking up-regulation of neuropeptide genes during dauer entry. We knocked down neuropeptide processing using sbt-1 mutants and demonstrate that neuropeptide signaling promotes the decision to enter dauer rather than reproductive development. We also demonstrate that during dauer neuropeptides modulate the dauer-specific nictation behavior (carrier animal-hitchhiking) and are necessary for switching from repulsion to CO_2 (a carrier animal cue) in nondauers to CO_2 attraction in dauers. We tested individual neuropeptides using CRISPR knockouts and existing strains and demonstrate that the combined effects of flp-10 and flp-17 mimic the effects of sbt-1on nictation and CO_2 attraction. Through meta-analysis, we discovered similar up-regulation of neuropeptides in the dauer-like infective juveniles of diverse parasitic nematodes, suggesting the antiparasitic target potential of SBT-1. Our findings reveal that, under stress, increased neuropeptide signaling in C. elegans enhances their decision-making accuracy and expands their behavioral repertoire.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle Information
Shih, Pei-Yin0000-0003-3082-9242
Quintero-Cadena, Porfirio0000-0003-0067-5844
Rogers, Alicia K.0000-0001-5525-6095
Sternberg, Paul W.0000-0002-7699-0173
Additional Information:© 2017 National Academy of Sciences. Published under the PNAS license. Contributed by Paul W. Sternberg, October 31, 2017 (sent for review June 8, 2017; reviewed by Junho Lee and Chris Li). Published online before print November 22, 2017. We thank Daehan Lee for providing the nictation microchip design; Elissa Hallem for advice on CO_2 assays; Christopher Cronin for advice on behavioral assay setups; Mihoko Kato, Hillel Schwartz, Igor Antoshechkin, Ryoji Shinya, Han Wang, Animesh Ray, and Jonathan Liu for critically reading the manuscript; the Caenorhabditis Genetics Center, which is funded by the NIH Office of Research Infrastructure Programs (Grant P40 OD010440), and Adam Antebi, Mario de Bono, and H. Robert Horvitz for providing animal strains; WormBase and WormBase SPELL for tools, datasets, and invaluable information; and the Millard and Muriel Jacobs Genetics and Genomics Laboratory for support with library construction and sequencing. Author contributions: J.S.L., P.-Y.S., O.N.S., and P.W.S. designed research; J.S.L., P.-Y.S., and O.N.S. performed research; J.S.L., P.-Y.S., O.N.S., and P.Q.-C. contributed new reagents/analytic tools; J.S.L., P.-Y.S., O.N.S., P.Q.-C., and A.K.R. analyzed data; and J.S.L., P.-Y.S., O.N.S., P.Q.-C., and P.W.S. wrote the paper. Reviewers: J.L., Seoul National University; and C.L., City College of New York. The authors declare no conflict of interest. Data deposition: The RNA-seq data in this paper have been deposited in the National Center for Biotechnology Information Sequence Read Archive (SRA) database (accession no. SRP116980). Codes used for data analysis have been deposited in GitHub and are available at This article contains supporting information online at
Group:Tianqiao and Chrissy Chen Institute for Neuroscience
Funding AgencyGrant Number
NIHP40 OD010440
Subject Keywords:phenotypic plasticity; RNA-seq; dauer; neuropeptide; FMRFamide
Issue or Number:50
PubMed Central ID:PMC5740649
Record Number:CaltechAUTHORS:20171127-073708419
Persistent URL:
Official Citation:James Siho Lee, Pei-Yin Shih, Oren N. Schaedel, Porfirio Quintero-Cadena, Alicia K. Rogers, and Paul W. Sternberg FMRFamide-like peptides expand the behavioral repertoire of a densely connected nervous system PNAS 2017 114 (50) E10726-E10735; published ahead of print November 22, 2017, doi:10.1073/pnas.1710374114
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:83434
Deposited By: Tony Diaz
Deposited On:27 Nov 2017 16:41
Last Modified:21 Mar 2022 16:51

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