Fhl2 interacts with Foxk1 and corepresses Foxo4 activity in myogenic progenitors.
Adult skeletal muscle has a remarkable regenerative capacity because of a myogenic progenitor cell population. Using a gene disruption strategy, we determined that Foxk1 regulates myogenic progenitor cell activation and muscle regeneration. In this study, we undertook a yeast two hybrid screen to identify Foxk1 interacting proteins. We identified the LIM-only protein, Fhl2, as a Foxk1 interacting protein. Using transcriptional assays, we observed that Fhl2, in a dose-dependent fashion, promotes Foxk1 transcriptional repression of Foxo4 activity. Using histochemical and immunohistochemical assays, we further established that Fhl2 is expressed in the myogenic progenitor cell population. Fhl2 knockdown results in cell cycle arrest, and mice lacking Fhl2 have perturbed skeletal muscle regeneration. Collectively, these studies define a Fhl2-Foxk1 cascade that regulates the myogenic progenitor cell activity in adult skeletal muscle and enhances our understanding of muscle regeneration.
Shi
Xiaozhong
X
Lillehei Heart Institute, University of Minnesota-Twin Cities, Minneapolis, Minnesota 55455, USA.
Bowlin
Kathy M
KM
Garry
Daniel J
DJ
D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D018816:Genes, cdc / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics*; D060850:LIM-Homeodomain Proteins; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
D018797:Cell Cycle Proteins; C491382:Fhl2 protein, mouse; D051858:Forkhead Transcription Factors; C525394:FoxO4 protein, mouse; C497672:Foxk1 protein, mouse; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D012097:Repressor Proteins; D014157:Transcription Factors