A Foxo/Notch pathway controls myogenic differentiation and fiber type specification.
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.
Kitamura
Tadahiro
T
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Kitamura
Yukari Ido
YI
Funahashi
Yasuhiro
Y
Shawber
Carrie J
CJ
Castrillon
Diego H
DH
Kollipara
Ramya
R
DePinho
Ronald A
RA
Kitajewski
Jan
J
Accili
Domenico
D
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D024510:Muscle Development; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D009124:Muscle Proteins; D009687:Nuclear Proteins; D051881:Receptor, Notch1; D014157:Transcription Factors; C467200:Foxo1 protein, mouse; C486455:Maml1 protein, mouse; C497762:Notch1 protein, mouse; C499035:Smpx protein, mouse
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