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A Foxo/Notch pathway controls myogenic differentiation and fiber type specification
Open accessAbstract
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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“previously reported role for FoxOs in cellular fate determination observed in myogenesis and hematopoiesis (Hu et al., 2008; Kitamura et al., 2007; Tothova et al., 2007).”
From FoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell Homeostasis (2009) · cites this paper as Kitamura et al., 2007
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Metadata
- 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
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2007-09-04
- Volume
- 117
- Issue
- 9
- Pages
- 2477-2485
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1950461
- 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
- bronze
- doi.org
- 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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