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Absence of p21CIP rescues myogenic progenitor cell proliferative and regenerative capacity in Foxk1 null mice
Thomas J Hawke1, Nan Jiang, Daniel J Garry
1Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas 75390-8573, USA.
Abstract:
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.
Insights
Foxk1 transcription factor is vital for skeletal muscle regeneration and cell cycle control in myogenic progenitor cells. Its absence causes growth defects, but restoring p21(CIP) levels reverses these effects.
Area of Science:
- Molecular Biology
- Developmental Biology
- Muscle Physiology
Background:
- Foxk1 (forkhead/winged helix transcription factor) is crucial for adult skeletal muscle progenitor cells.
- Mice lacking Foxk1 exhibit impaired muscle regeneration and growth retardation.
- Myogenic progenitor cells in Foxk1-deficient mice show reduced numbers and cell cycle arrest.
Purpose of the Study:
- To investigate the role of Foxk1 in myogenic progenitor cell cycle regulation.
- To identify downstream targets of Foxk1 in skeletal muscle regeneration.
- To determine the necessity of p21(CIP) in Foxk1-mediated cellular processes.
Main Methods:
- Analysis of Foxk1-deficient mouse models.
- Cell cycle analysis of myogenic progenitor cells.
- Genetic manipulation using combinatorial mating of knockout mice.
Main Results:
- Foxk1 deficiency leads to G(0)/G(1) cell cycle arrest in myogenic progenitor cells.
- Increased p21(CIP) expression was observed in Foxk1-null cells, independent of p53.
- Double knockout mice (Foxk1-/- and p21(CIP)-/-) showed complete restoration of growth and muscle regeneration.
Conclusions:
- Foxk1 is essential for regulating cell cycle progression in myogenic progenitor cells.
- The cyclin-dependent kinase inhibitor p21(CIP) is a key downstream target of Foxk1.
- Targeting Foxk1 or p21(CIP) may offer therapeutic strategies for muscle regeneration.
