GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway

Hidekazu Ishida, Rie Saba, Ioannis Kokkinopoulos, Masakazu Hashimoto, Osamu Yamaguchi, Sonja Nowotschin, Manabu Shiraishi, Prashant Ruchaya, Duncan Miller, Stephen Harmer, Ariel Poliandri, Shigetoyo Kogaki, Yasushi Sakata, Leo Dunkel, Andrew Tinker, Anna-Katerina Hadjantonakis, Yoshiki Sawa, Hiroshi Sasaki, Keiichi Ozono, Ken SuzukiKenta Yashiro

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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.

Original languageEnglish
Pages (from-to)1026-1038
Number of pages13
JournalCell Reports
Issue number4
Early online date26 Jul 2016
Publication statusPublished - 26 Jul 2016

Bibliographical note

Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.


  • Animals
  • Cell Differentiation/physiology
  • Cells, Cultured
  • Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism
  • Glycosylphosphatidylinositols/metabolism
  • Humans
  • Ligands
  • Mice
  • Myocytes, Cardiac/metabolism
  • Organogenesis/physiology
  • Pluripotent Stem Cells/metabolism
  • Proto-Oncogene Proteins c-ret/metabolism
  • Receptor Protein-Tyrosine Kinases/metabolism
  • Signal Transduction/physiology


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