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Epidermal growth factor signaling induces behavioral quiescence in Caenorhabditis elegans

Abstract

The epidermal growth factor receptor (EGFR)/ErbB receptor tyrosine kinases regulate several aspects of development, including the development of the mammalian nervous system. ErbB signaling also has physiological effects on neuronal function, with influences on synaptic plasticity and daily cycles of activity. However, little is known about the effectors of EGFR activation in neurons. Here we show that EGF signaling has a nondevelopmental effect on behavior in Caenorhabditis elegans. Ectopic expression of the EGF-like ligand LIN-3 at any stage induces a reversible cessation of feeding and locomotion. These effects are mediated by neuronal EGFR (also called LET-23) and phospholipase C–γ (PLC-γ), diacylglycerol-binding proteins, and regulators of synaptic vesicle release. Activation of EGFR within a single neuron, ALA, is sufficient to induce a quiescent state. This pathway modulates the cessation of pharyngeal pumping and locomotion that normally occurs during the lethargus period that precedes larval molting. Our results reveal an evolutionarily conserved role for EGF signaling in the regulation of behavioral quiescence.

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Figure 1: The hs:LIN-3 movement defect is mediated by LET-23, PLC-γ and EGL-4.
Figure 2: LET-23 and PLC-γ act in neurons to mediate the hs:LIN-3 movement defect.
Figure 3: LET-23 activity in the ALA neuron mediates the behavioral effects of LIN-3.
Figure 4: let-23 and plc-3 mutants show increased activity during lethargus.

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Acknowledgements

We thank the Caenorhabditis Genetics Center for providing strains, S. Kim (Stanford University School of Medicine) for anti-LET-23 antibody, J. DeModena for antibody staining, S. Xu (Univ. Michigan) for the plc-3(sy698) allele, S. Mitani (Tokyo Women's Medical University School of Medicine) for the plc-3(tm1340) allele, N. Moghal, M. Kato, and S. Xu for critical reading of the manuscript, and C.J. Cronin for help with the automated tracking system and locomotion data analysis. This work was supported by a California Breast Cancer Research Program fellowship to C.V.B., by a US National Institute on Drug Abuse grant (DA018341) to P.W.S., and by the Howard Hughes Medical Institute, with which C.V.B. is an Associate and P.W.S. is an Investigator.

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C.V.B. designed and conducted the experiments and wrote the manuscript; P.W.S. supervised the project.

Corresponding author

Correspondence to Paul W Sternberg.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4, Tables 1–4, and Methods (PDF 2524 kb)

Supplementary Video 1

Wild-type pharyngeal pumping (MOV 651 kb)

Supplementary Video 2

hs:LIN-3 inhibits pharyngeal pumping (MOV 823 kb)

Supplementary Video 3

Wild-type locomotion (MOV 2327 kb)

Supplementary Video 4

hs:LIN-3 severely impairs locomotion (MOV 2357 kb)

Supplementary Video 5

LIN-3 animals move normally when prodded (MOV 2135 kb)

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Van Buskirk, C., Sternberg, P. Epidermal growth factor signaling induces behavioral quiescence in Caenorhabditis elegans. Nat Neurosci 10, 1300–1307 (2007). https://doi.org/10.1038/nn1981

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