title: Differentially timed extracellular signals synchronize pacemaker neuron clocks.
abstract: Synchronized neuronal activity is vital for complex processes like behavior. Circadian pacemaker neurons offer an unusual opportunity to study synchrony as their molecular clocks oscillate in phase over an extended timeframe (24 h). To identify where, when, and how synchronizing signals are perceived, we first studied the minimal clock neural circuit in Drosophila larvae, manipulating either the four master pacemaker neurons (LNvs) or two dorsal clock neurons (DN1s). Unexpectedly, we found that the PDF Receptor (PdfR) is required in both LNvs and DN1s to maintain synchronized LNv clocks. We also found that glutamate is a second synchronizing signal that is released from DN1s and perceived in LNvs via the metabotropic glutamate receptor (mGluRA). Because simultaneously reducing Pdfr and mGluRA expression in LNvs severely dampened Timeless clock protein oscillations, we conclude that the master pacemaker LNvs require extracellular signals to function normally. These two synchronizing signals are released at opposite times of day and drive cAMP oscillations in LNvs. Finally we found that PdfR and mGluRA also help synchronize Timeless oscillations in adult s-LNvs. We propose that differentially timed signals that drive cAMP oscillations and synchronize pacemaker neurons in circadian neural circuits will be conserved across species.
authors.affiliation: Department of Biology, New York University, New York, New York, United States of America.
authors.forename: Ben
authors.initials: B
authors.lastname: Collins
authors.affiliation: Department of Biology, New York University, New York, New York, United States of America.
authors.forename: Harris S
authors.initials: HS
authors.lastname: Kaplan
authors.affiliation: Department of Biology, New York University, New York, New York, United States of America.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Cavey
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Lelito
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Bahle
authors.affiliation: Department of Biology, New York University, New York, New York, United States of America.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Macara
authors.affiliation: Department of Biology and Biochemistry, University of Houston, Houston, Texas, United States of America.
authors.forename: Gregg
authors.initials: G
authors.lastname: Roman
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Orie T
authors.initials: OT
authors.lastname: Shafer
authors.affiliation: Department of Biology, New York University, New York, New York, United States of America; Center for Genomics & Systems Biology, New York University Abu Dhabi Institute, Abu Dhabi, United Arab Emirates; Program in Biology, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
authors.forename: Justin
authors.initials: J
authors.lastname: Blau
mesh_terms: D000818:Animals; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000378:metabolism; D007814:Larva / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D017440:Photoperiod; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D029721:Drosophila Proteins; D009479:Neuropeptides; C507073:PDFR protein, Drosophila; D043562:Receptors, G-Protein-Coupled; D018094:Receptors, Metabotropic Glutamate; C494781:mGluR protein, Drosophila; C113883:pdf protein, Drosophila; C096445:tim protein, Drosophila; D018698:Glutamic Acid; D000242:Cyclic AMP