Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
A Foxo/Notch pathway controls myogenic differentiation and fiber type specification
Tadahiro Kitamura, … , Jan Kitajewski, Domenico Accili
Tadahiro Kitamura, … , Jan Kitajewski, Domenico Accili
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2477-2485. https://doi.org/10.1172/JCI32054.
View: Text | PDF
Research Article Development

A Foxo/Notch pathway controls myogenic differentiation and fiber type specification

  • Text
  • PDF
Abstract

Forkhead box O (Foxo) transcription factors govern metabolism and cellular differentiation. Unlike Foxo-dependent metabolic pathways and target genes, the mechanisms by which these proteins regulate differentiation have not been explored. Activation of Notch signaling mimics the effects of Foxo gain of function on cellular differentiation. Using muscle differentiation as a model system, we show that Foxo physically and functionally interacts with Notch by promoting corepressor clearance from the Notch effector Csl, leading to activation of Notch target genes. Inhibition of myoblast differentiation by constitutively active Foxo1 is partly rescued by inhibition of Notch signaling while Foxo1 loss of function precludes Notch inhibition of myogenesis and increases myogenic determination gene (MyoD) expression. Accordingly, conditional Foxo1 ablation in skeletal muscle results in increased formation of MyoD-containing (fast-twitch) muscle fibers and altered fiber type distribution at the expense of myogenin-containing (slow-twitch) fibers. Notch/Foxo1 cooperation may integrate environmental cues through Notch with metabolic cues through Foxo1 to regulate progenitor cell maintenance and differentiation.

Authors

Tadahiro Kitamura, Yukari Ido Kitamura, Yasuhiro Funahashi, Carrie J. Shawber, Diego H. Castrillon, Ramya Kollipara, Ronald A. DePinho, Jan Kitajewski, Domenico Accili

×

Figure 6

Foxo1 is required for Notch binding to the Hes1 promoter and activation of Hes1 target genes.

Options: View larger image (or click on image) Download as PowerPoint
Foxo1 is required for Notch binding to the Hes1 promoter and activation ...
(A) ChIP assays of endogenous Foxo1 and Notch1 in C2C12 cells cocultured with LacZ-expressing (denoted by a minus sign) or Jagged1-expressing HEK293 cells (denoted by a plus sign) in the absence (lanes 1 and 2) and presence (lanes 3 and 4) of Csl siRNA. (B) ChIP assays of endogenous Notch1 in coculture system in the absence (lanes 1 and 2) and presence (lanes 3 and 4) of Foxo1 siRNA. (C) Hes1 promoter assays following coculture in the absence and presence of Foxo1 or GFP siRNA. (D) ChIP assays of NcoR and Smrt and Maml1 binding to Hes1 in the coculture system in the absence (lanes 1 and 2) and presence (lanes 3 and 4) of Foxo1 siRNA. (E) Expression of MyoD, Myf5, and β-actin in C2C12 cells by semiquantitative RT-PCR. (F) Model of Foxo1 and Notch regulation of Hes1 promoter.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts