Absence of p21CIP rescues myogenic progenitor cell proliferative and regenerative capacity in Foxk1 null mice.
Foxk1 is a forkhead/winged helix transcription factor that is restricted to myogenic progenitor cells in adult skeletal muscle. Mice lacking Foxk1 (Foxk1-/-) display growth retardation and a severe impairment in skeletal muscle regeneration following injury. Here we show that myogenic progenitor cells from Foxk1-/- mice are reduced in number and have perturbed cell cycle progression (G(0)/G(1) arrest). Molecular analysis of Foxk1-/- myogenic progenitor cells revealed increased expression of the cyclin-dependent kinase inhibitor, p21(CIP), independent of changes in other cell cycle inhibitors, including p53. Combinatorial mating of Foxk1-/- mice with p21(CIP)-/- mice, to generate double mutant progeny, resulted in a complete restoration of the growth deficit, skeletal muscle regeneration, myogenic progenitor cell number, and cell cycle progression that characterized the Foxk1-/- mice. We conclude that Foxk1 is essential for regulating cell cycle progression in the myogenic progenitor cell and that the cyclin-dependent kinase inhibitor, p21(CIP), may be a downstream target of Foxk1.
Hawke
Thomas J
TJ
Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas 75390-8573, USA.
Jiang
Nan
N
Garry
Daniel J
DJ
D000818:Animals; D002455:Cell Division / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology*; D051858:Forkhead Transcription Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000166:cytology* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D012038:Regeneration / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D051858:Forkhead Transcription Factors; C497672:Foxk1 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors