title: Decoy receptor CXCR7 modulates adrenomedullin-mediated cardiac and lymphatic vascular development.
abstract: Atypical 7-transmembrane receptors, often called decoy receptors, act promiscuously as molecular sinks to regulate ligand bioavailability and consequently temper the signaling of canonical G protein-coupled receptor (GPCR) pathways. Loss of mammalian CXCR7, the most recently described decoy receptor, results in postnatal lethality due to aberrant cardiac development and myocyte hyperplasia. Here, we provide the molecular underpinning for this proliferative phenotype by demonstrating that the dosage and signaling of adrenomedullin (Adm, gene; AM, protein)-a mitogenic peptide hormone required for normal cardiovascular development-is tightly controlled by CXCR7. To this end, Cxcr7(-/-) mice exhibit gain-of-function cardiac and lymphatic vascular phenotypes that can be reversed upon genetic depletion of adrenomedullin ligand. In addition to identifying a biological ligand accountable for the phenotypes of Cxcr7(-/-) mice, these results reveal a previously underappreciated role for decoy receptors as molecular rheostats in controlling the timing and extent of GPCR-mediated cardiac and vascular development.
authors.affiliation: Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Klara R
authors.initials: KR
authors.lastname: Klein
authors.affiliation: Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Natalie O
authors.initials: NO
authors.lastname: Karpinich
authors.affiliation: Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Espenschied
authors.affiliation: Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Helen H
authors.initials: HH
authors.lastname: Willcockson
authors.affiliation: Department of Genetics, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Dunworth
authors.affiliation: Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Hoopes
authors.affiliation: Department of Biology, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Erich J
authors.initials: EJ
authors.lastname: Kushner
authors.affiliation: Department of Biology, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bautch
authors.affiliation: Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, NC 27599, USA; Department of Genetics, The University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: kathleen_caron@med.unc.edu.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Caron
mesh_terms: D053607:Adrenomedullin / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006321:Heart / Q000196:embryology*; D006801:Humans; D008024:Ligands; D042601:Lymphatic Vessels / Q000196:embryology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000166:cytology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D054387:Receptors, CXCR / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C501897:Cmkor1 protein, mouse; D008024:Ligands; D054387:Receptors, CXCR; D053607:Adrenomedullin