title: GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway.
abstract: A surface marker that distinctly identifies cardiac progenitors (CPs) is essential for the robust isolation of these cells, circumventing the necessity of genetic modification. Here, we demonstrate that a Glycosylphosphatidylinositol-anchor containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 (Gfra2), specifically marks CPs. GFRA2 expression facilitates the isolation of CPs by fluorescence activated cell sorting from differentiating mouse and human pluripotent stem cells. Gfra2 mutants reveal an important role for GFRA2 in cardiomyocyte differentiation and development both in vitro and in vivo. Mechanistically, the cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase and its established ligands. Collectively, our findings establish a platform for investigating the biology of CPs as a foundation for future development of CP transplantation for treating heart failure.
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Department of Paediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Ishida
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Rie
authors.initials: R
authors.lastname: Saba
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kokkinopoulos
authors.affiliation: Laboratory for Embryogenesis, Osaka University Graduate School of Frontier Biosciences, Osaka 565-0871, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamaguchi
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Nowotschin
authors.affiliation: Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Manabu
authors.initials: M
authors.lastname: Shiraishi
authors.affiliation: Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Centre of Human and Aerospace Physiological Sciences, School of Biomedical Sciences, King's College, London, SE1 1UL, UK.
authors.forename: Prashant
authors.initials: P
authors.lastname: Ruchaya
authors.affiliation: Cardiac Electrophysiology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: Miller
authors.affiliation: Cardiac Electrophysiology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Harmer
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Ariel
authors.initials: A
authors.lastname: Poliandri
authors.affiliation: Department of Paediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Shigetoyo
authors.initials: S
authors.lastname: Kogaki
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Leo
authors.initials: L
authors.lastname: Dunkel
authors.affiliation: Cardiac Electrophysiology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tinker
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Anna-Katerina
authors.initials: AK
authors.lastname: Hadjantonakis
authors.affiliation: Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
authors.affiliation: Laboratory for Embryogenesis, Osaka University Graduate School of Frontier Biosciences, Osaka 565-0871, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Department of Paediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
authors.affiliation: Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Ken
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. Electronic address: drkyashiro@gmail.com.
authors.forename: Kenta
authors.initials: K
authors.lastname: Yashiro
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism*; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D038081:Organogenesis / Q000502:physiology; D039904:Pluripotent Stem Cells / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C494990:GFRA2 protein, human; C494991:Gfra2 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D017261:Glycosylphosphatidylinositols; D008024:Ligands; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases; C494999:Ret protein, mouse