title: Nuclear to cytoplasmic shuttling of ERK promotes differentiation of muscle stem/progenitor cells.
abstract: The transition between the proliferation and differentiation of progenitor cells is a key step in organogenesis, and alterations in this process can lead to developmental disorders. The extracellular signal-regulated kinase 1/2 (ERK) signaling pathway is one of the most intensively studied signaling mechanisms that regulates both proliferation and differentiation. How a single molecule (e.g. ERK) can regulate two opposing cellular outcomes is still a mystery. Using both chick and mouse models, we shed light on the mechanism responsible for the switch from proliferation to differentiation of head muscle progenitors and implicate ERK subcellular localization. Manipulation of the fibroblast growth factor (FGF)-ERK signaling pathway in chick embryos in vitro and in vivo demonstrated that blockage of this pathway accelerated myogenic differentiation, whereas its activation diminished it. We next examined whether the spatial subcellular localization of ERK could act as a switch between proliferation (nuclear ERK) and differentiation (cytoplasmic ERK) of muscle progenitors. A myristoylated peptide that blocks importin 7-mediated ERK nuclear translocation induced robust myogenic differentiation of muscle progenitor/stem cells in both head and trunk. In the mouse, analysis of Sprouty mutant embryos revealed that increased ERK signaling suppressed both head and trunk myogenesis. Our findings, corroborated by mathematical modeling, suggest that ERK shuttling between the nucleus and the cytoplasm provides a switch-like transition between proliferation and differentiation of muscle progenitors.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Inbal
authors.initials: I
authors.lastname: Michailovici
authors.affiliation: Theoretical Systems Biology, Division of Molecular Biosciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Harrington
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Hadar Hay
authors.initials: HH
authors.lastname: Azogui
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Yfat
authors.initials: Y
authors.lastname: Yahalom-Ronen
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Plotnikov
authors.affiliation: Department of Orofacial Sciences and Program in Craniofacial and Mesenchymal Biology, University of California San Francisco, San Francisco, CA 94143-0430, USA.
authors.forename: Saunders
authors.initials: S
authors.lastname: Ching
authors.affiliation: Theoretical Systems Biology, Division of Molecular Biosciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Michael P H
authors.initials: MP
authors.lastname: Stumpf
authors.affiliation: Department of Orofacial Sciences and Program in Craniofacial and Mesenchymal Biology, University of California San Francisco, San Francisco, CA 94143-0430, USA Department of Pediatrics, Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143-0442, USA.
authors.forename: Ophir D
authors.initials: OD
authors.lastname: Klein
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Rony
authors.initials: R
authors.lastname: Seger
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel eldad.tzahor@weizmann.ac.il.
authors.forename: Eldad
authors.initials: E
authors.lastname: Tzahor
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002642:Chick Embryo; D017931:DNA Primers / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D024510:Muscle Development / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D013234:Stem Cells / Q000502:physiology*
chemical_list: D017931:DNA Primers; D048049:Extracellular Signal-Regulated MAP Kinases; D001973:Bromodeoxyuridine
keywords: Chick; ERK; FGF signaling; Mouse; Myogenesis