Cited by 285Muscle Physiology and DisordersFOXO transcription factor regulationDevelopmental Biology and Gene Regulation

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

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Kitamura, Tadahiro, Kitamura, Yukari Ido, Funahashi, Yasuhiro, Shawber, Carrie J., Castrillon, Diego H., Kollipara, Ramya, DePinho, Ronald A., Kitajewski, Jan +1 more·2007·Journal of Clinical Investigation

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.

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Authors
Kitamura, T., Kitamura, Y. I., Funahashi, Y., Shawber, C. J., Castrillon, D. H., Kollipara, R., DePinho, R. A., Kitajewski, J., & Accili, D.
Affiliations
  • Gunma University (JP)
  • Columbia University (US)
  • Harvard University (US)
Corresponding author
Accili, Domenico
Venue
Journal of Clinical Investigation
Published
2007-09-04
Volume
117
Issue
9
Pages
2477-2485
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2045736879
Cited by
285
References
54
Citations by year
2026: 6 · 2025: 13 · 2024: 15 · 2023: 7 · 2022: 16 · 2021: 13 · 2020: 13 · 2019: 10 · 2018: 9 · 2017: 17 · 2016: 14 · 2015: 12 · 2014: 18 · 2013: 18 · 2012: 31
FWCI
6.50
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (DK63608, DK57539)
  • National Heart, Lung, and Blood Institute (R01HL062454)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK057539, DK63608, K01DK074629, DK-64819, DK 57539, P30DK063608, R01DK064819)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
FOXO1, Notch signaling, myogenesis, MyoD, myogenin, CSL transcription factor, fast-twitch muscle, slow-twitch muscle, transcriptional regulation
MeSH terms
Forkhead Box Protein O1, Animals, Cell Differentiation, Cell Line, Gene Expression Regulation, Mice, Transgenic, Muscle Proteins, Nuclear Proteins, Promoter Regions, Genetic, Protein Binding, Transcription Factors, Signal Transduction, Muscle, Skeletal, Muscle Development, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Forkhead Transcription Factors, Receptor, Notch1

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