title: Serum Proteases Potentiate BMP-Induced Cell Cycle Re-entry of Dedifferentiating Muscle Cells during Newt Limb Regeneration.
abstract: Limb amputation in the newt induces myofibers to dedifferentiate and re-enter the cell cycle to generate proliferative myogenic precursors in the regeneration blastema. Here we show that bone morphogenetic proteins (BMPs) and mature BMPs that have been further cleaved by serum proteases induce cell cycle entry by dedifferentiating newt muscle cells. Protease-activated BMP4/7 heterodimers that are present in serum strongly induced myotube cell cycle re-entry with protease cleavage yielding a 30-fold potency increase of BMP4/7 compared with canonical BMP4/7. Inhibition of BMP signaling via muscle-specific dominant-negative receptor expression reduced cell cycle entry in vitro and in vivo. In vivo inhibition of serine protease activity depressed cell cycle re-entry, which in turn was rescued by cleaved-mimic BMP. This work identifies a mechanism of BMP activation that generates blastema cells from differentiated muscle.
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany; DFG Research Center for Regenerative Therapies, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Wagner
authors.affiliation: Department of Cell and Molecular Biology, Centre of Developmental Biology for Regenerative Medicine, Karolinska Institute, Berzelius väg 35, 17177 Stockholm, Sweden.
authors.forename: Heng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany; DFG Research Center for Regenerative Therapies, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Weissert
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
authors.forename: Werner L
authors.initials: WL
authors.lastname: Straube
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Shevchenko
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Gentzel
authors.affiliation: Department of Cell and Molecular Biology, Centre of Developmental Biology for Regenerative Medicine, Karolinska Institute, Berzelius väg 35, 17177 Stockholm, Sweden.
authors.forename: Goncalo
authors.initials: G
authors.lastname: Brito
authors.affiliation: DFG Research Center for Regenerative Therapies, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
authors.forename: Akira
authors.initials: A
authors.lastname: Tazaki
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany; DFG Research Center for Regenerative Therapies, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
authors.forename: Catarina
authors.initials: C
authors.lastname: Oliveira
authors.affiliation: DFG Research Center for Regenerative Therapies, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
authors.forename: Takuji
authors.initials: T
authors.lastname: Sugiura
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
authors.forename: Andrej
authors.initials: A
authors.lastname: Shevchenko
authors.affiliation: Department of Cell and Molecular Biology, Centre of Developmental Biology for Regenerative Medicine, Karolinska Institute, Berzelius väg 35, 17177 Stockholm, Sweden. Electronic address: andras.simon@ki.se.
authors.forename: András
authors.initials: A
authors.lastname: Simon
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany. Electronic address: david.drechsel@imp.ac.at.
authors.forename: David N
authors.initials: DN
authors.lastname: Drechsel
authors.affiliation: DFG Research Center for Regenerative Therapies, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany. Electronic address: elly.tanaka@imp.ac.at.
authors.forename: Elly M
authors.initials: EM
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects*; D054337:Cell Dedifferentiation / Q000187:drug effects*; D005121:Extremities / Q000502:physiology*; D005341:Fibrinolysin / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D032342:Muscle Cells / Q000166:cytology* / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D010447:Peptide Hydrolases / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects*; D016196:S Phase / Q000187:drug effects; D012455:Salamandridae / Q000502:physiology*; D044967:Serum / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology
chemical_list: D019485:Bone Morphogenetic Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D051785:Smad Proteins; D010447:Peptide Hydrolases; D013917:Thrombin; D005341:Fibrinolysin
keywords: BMP (bone morphogenetic protein); cell cycle re-entry; dedifferentiation; limb regeneration; muscle; plasmin; salamander; thrombin