Triggering and modulation of a complex behavior by a single peptidergic command neuron in Drosophila
Edited by Eve Marder, Brandeis University, Waltham, MA; received October 5, 2024; accepted February 13, 2025
Significance
At the end of their growth phase, Drosophila larvae remodel their bodies, glue themselves to a substrate, and harden their cuticle in preparation for metamorphosis. This multistep motor program is called pupariation. Little is known about its neural basis. Here, we find that a pair of descending neurons electrically activates and partially orchestrates the pupariation behavior subunit required for substrate attachment, the glue expulsion and spreading behavior (GSB). These same GSB command neurons use a conserved neuropeptidergic signaling pathway (Mip-SPR signaling pathway) to fine-tune GSB components and their timing via SPR-positive interneurons in the ventral nerve cord. Our work opens the way to dissecting the pupariation neural network up- and downstream of this GSB circuit.
Abstract
At the end of their growth phase, Drosophila larvae remodel their bodies, glue themselves to a substrate, and harden their cuticle in preparation for metamorphosis. This process—termed pupariation—is triggered by a surge in the hormone ecdysone. Substrate attachment is achieved by a pupariation subprogram called glue expulsion and spreading behavior (GSB). An epidermis-to-CNS Dilp8-Lgr3 relaxin signaling event that occurs downstream of ecdysone is critical for unlocking progression of the pupariation motor program toward GSB, but the factors and circuits acting downstream of Lgr3 signaling remain unknown. Here, using cell-type-specific RNA interference and behavioral monitoring, we identify Myoinhibiting peptide (Mip) as a neuromodulator of multiple GSB action components, such as tetanic contraction, peristaltic contraction alternation, and head-waving. Mip is required in a pair of brain descending neurons, which act temporally downstream of Dilp8-Lgr3 signaling. Mip modulates GSB via ventral nerve cord neurons expressing its conserved receptor, sex peptide receptor (SPR). Silencing of Mip descending neurons by hyperpolarization completely abrogates GSB, while their optogenetic activation at a restricted competence time window triggers GSB-like behavior. Hence, Mip descending neurons have at least two functions: to act as GSB command neurons and to secrete Mip to modulate GSB action components. Our results provide insight into conserved aspects of Mip-SPR signaling in animals, reveal the complexity of GSB control, and contribute to the understanding of how multistep innate behaviors are coordinated in time and with other developmental processes through command neurons and neuropeptidergic signaling.
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Data, Materials, and Software Availability
Scripts’ data have been deposited in GitHub (85). All other data are included in the manuscript and/or supporting information.
Acknowledgments
We thank Drs. Carlos Ribeiro, Nara Muraro, Fernanda Ceriani, and Mariana Melani for fly stocks and reagents. We thank lab members for discussions and/or comments on the manuscript. We thank Carolina Gomila for technical assistance. Stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) and Vienna Drosophila Resource Center were used in this study. Work in the Integrative Biomedicine Laboratory was supported by the Fundação para a Ciência e a Tecnologia (FCT) (PTDC/BIA-BID/31071/2017; PTDC/MED-NEU/30753/2017 (LISBOA-01-0145-FEDER-030753, with financing from the Programa Operacional Lisboa 2020); EXPL/BIA-BID/1524/2021; EXPL/BIA-COM/1296/2021; 10.54499/2022.03859.PTDC; 2023.15344.PEX), by the Research and Development Units iNOVA4Health (10.54499/UIDB/04462/2020) and Centre for Ecology, Evolution and Environmental Changes (cE3c) (10.54499/UIDB/00329/2020), by LS4FUTURE and CHANGE financed by the FCT/Ministério da Ciência, Tecnologia e Ensino Superior (Portugal), by Congento LISBOA-01-0145-FEDER-022170, cofinanced by FCT/Lisboa2020; UID/Multi/04462/2019, and by the Microscopy Facility of Faculdade de Ciências da Universidade de Lisboa (PPBI-POCI-01-0145-FEDER-022122). Work in the Garelli lab was supported by Agencia Nacional de Promoción Científica y Tecnológica (PICT-2017-0254 and PICT-2020-01568), Consejo Nacional de Investigaciones Científicas y Técnicas (PIP11220150100182CO), and UNS-PGI-24/B288. The generation of Mip-GAL4 lines was supported by the Deutsche Forschungsgemeinschaft (DFG WE 2652/4-1,2, to C.W.). A.M.G. and F.H. were individually supported by Grants 10.54499/CEECINST/00102/2018/CP1567/CT0031 and 10.54499/DL57/2016/CP1457/CT0016, respectively. A.G. and Y.A.V. are CONICET researchers. M.A. and M.S.P. held a CONICET doctoral fellowship and J.I. an undergraduate fellowship from Consejo Interuniversitario Nacional. All reagents and fly strains generated in this study are available from the corresponding authors without restriction.
Author contributions
F.H., A.M.G., and A.G. designed research; M.F.-A., R.Z., F.H., Y.A.V., J.M., K.P., J.I., M.A., M.S.P., A.M.G., and A.G. performed research; J.A.V. and C.W. contributed new reagents/analytic tools; M.F.-A., R.Z., F.H., Y.A.V., J.M., K.P., J.I., M.A., M.S.P., J.A.V., A.M.G., and A.G. analyzed data; J.A.V. and C.W. contributed to drafting and revisions; and A.M.G. and A.G. wrote the paper.
Competing interests
The authors declare no competing interest.
Supporting Information
Appendix 01 (PDF)
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Movie S1.
Example of videos of larvae performing a normal (top, R48H10>+) and abnormal GSB (bottom, R48H10>Mip-IR) recorded in the pupariation monitor device during the screen and synchronized at the beginning of GSB. Occurrence of pre-GSB contractions is indicated with a yellow hyphen and helps to identify the moment when GSB is expected to occur in those larvae with abnormal or absent GSB. The dashed silhouette marks the starting position of each larva. Larvae usually move forward about one third the length of their body during GSB. Video reproduced at 3X speed.
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Movie S2.
Footage of Mip2M>ReaChR larvae doing a light induced GSB followed by a spontaneous GSB within the five minute-long unstimulated period, demonstrating that larval response to light constitute a separate behavioral event. Video reproduced at 4x speed. Time of spontaneous GSB: Left, 01:52; center and right, 01:20
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Movie S3.
Wandering larvae fed with 100 μM all-trans retinal (ATR) were stimulated with 10 pulses of green light of 0.5 seconds of duration at 1 Hz. Control larvae not fed with ATR did not respond to light, while those supplemented did a GSB-like behavior.
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- 2.50 MB
Movie S4.
Example of videos of larvae showing muscle GCaMP fluctuations performing a normal (left, wild type) and abnormal GSB (right, Mip1 null mutant). Wild type animals display the whole GSB behavioral sequence. It begins with a tetanic contraction of the anterior segments that expels glue from the salivary glands, followed by back-and-forth peristaltic waves that spread it over the ventral surface. GSB culminates with a “head waving” movement. Larvae that lack Mip neuropeptide can still initiate GSB, but it primarily consists of backwards movements.
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Copyright © 2025 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Data, Materials, and Software Availability
Scripts’ data have been deposited in GitHub (85). All other data are included in the manuscript and/or supporting information.
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Received: October 5, 2024
Accepted: February 13, 2025
Published online: March 14, 2025
Published in issue: March 18, 2025
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Acknowledgments
We thank Drs. Carlos Ribeiro, Nara Muraro, Fernanda Ceriani, and Mariana Melani for fly stocks and reagents. We thank lab members for discussions and/or comments on the manuscript. We thank Carolina Gomila for technical assistance. Stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) and Vienna Drosophila Resource Center were used in this study. Work in the Integrative Biomedicine Laboratory was supported by the Fundação para a Ciência e a Tecnologia (FCT) (PTDC/BIA-BID/31071/2017; PTDC/MED-NEU/30753/2017 (LISBOA-01-0145-FEDER-030753, with financing from the Programa Operacional Lisboa 2020); EXPL/BIA-BID/1524/2021; EXPL/BIA-COM/1296/2021; 10.54499/2022.03859.PTDC; 2023.15344.PEX), by the Research and Development Units iNOVA4Health (10.54499/UIDB/04462/2020) and Centre for Ecology, Evolution and Environmental Changes (cE3c) (10.54499/UIDB/00329/2020), by LS4FUTURE and CHANGE financed by the FCT/Ministério da Ciência, Tecnologia e Ensino Superior (Portugal), by Congento LISBOA-01-0145-FEDER-022170, cofinanced by FCT/Lisboa2020; UID/Multi/04462/2019, and by the Microscopy Facility of Faculdade de Ciências da Universidade de Lisboa (PPBI-POCI-01-0145-FEDER-022122). Work in the Garelli lab was supported by Agencia Nacional de Promoción Científica y Tecnológica (PICT-2017-0254 and PICT-2020-01568), Consejo Nacional de Investigaciones Científicas y Técnicas (PIP11220150100182CO), and UNS-PGI-24/B288. The generation of Mip-GAL4 lines was supported by the Deutsche Forschungsgemeinschaft (DFG WE 2652/4-1,2, to C.W.). A.M.G. and F.H. were individually supported by Grants 10.54499/CEECINST/00102/2018/CP1567/CT0031 and 10.54499/DL57/2016/CP1457/CT0016, respectively. A.G. and Y.A.V. are CONICET researchers. M.A. and M.S.P. held a CONICET doctoral fellowship and J.I. an undergraduate fellowship from Consejo Interuniversitario Nacional. All reagents and fly strains generated in this study are available from the corresponding authors without restriction.
Author contributions
F.H., A.M.G., and A.G. designed research; M.F.-A., R.Z., F.H., Y.A.V., J.M., K.P., J.I., M.A., M.S.P., A.M.G., and A.G. performed research; J.A.V. and C.W. contributed new reagents/analytic tools; M.F.-A., R.Z., F.H., Y.A.V., J.M., K.P., J.I., M.A., M.S.P., J.A.V., A.M.G., and A.G. analyzed data; J.A.V. and C.W. contributed to drafting and revisions; and A.M.G. and A.G. wrote the paper.
Competing interests
The authors declare no competing interest.
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Triggering and modulation of a complex behavior by a single peptidergic command neuron in Drosophila, Proc. Natl. Acad. Sci. U.S.A.
122 (11) e2420452122,
https://doi.org/10.1073/pnas.2420452122
(2025).
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