A Critical Requirement for Notch Signaling in Maintenance of the Quiescent Skeletal Muscle Stem Cell State

Notch signaling plays a key role in virtually all tissues and organs in metazoans; however, limited examples are available for the regulatory role of this pathway in adult quiescent stem cells. We performed a temporal and ontological assessment of effectors of the Notch pathway that indicated highes...

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Bibliographic Details
Published in:Stem cells (Dayton, Ohio) Ohio), 2012-02, Vol.30 (2), p.243-252
Main Authors: Mourikis, Philippos, Sambasivan, Ramkumar, Castel, David, Rocheteau, Pierre, Bizzarro, Valentina, Tajbakhsh, Shahragim
Format: Article
Language:English
Subjects:
Animals
Cell Cycle Checkpoints
Cell Differentiation
Cell Lineage
Gene Expression Profiling
Immunoglobulin J Recombination Signal Sequence-Binding Protein - genetics
Mice
Mice, Knockout
Muscle Development
Muscle stem cell
Muscle, Skeletal - cytology
Muscle, Skeletal - metabolism
Muscle, Skeletal - physiology
Mutation
Notch
Oligonucleotide Array Sequence Analysis
Quiescence
Rbpj
Receptors, Notch - metabolism
Regeneration
S Phase
Satellite cell
Satellite Cells, Skeletal Muscle - metabolism
Signal Transduction
Stem cells
Stem Cells - metabolism
Stem Cells - physiology
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Summary:Notch signaling plays a key role in virtually all tissues and organs in metazoans; however, limited examples are available for the regulatory role of this pathway in adult quiescent stem cells. We performed a temporal and ontological assessment of effectors of the Notch pathway that indicated highest activity in freshly isolated satellite cells and, unexpectedly, a sharp decline before the first mitosis, and subsequently in proliferating, satellite cell‐derived myoblasts. Using genetic tools to conditionally abrogate canonical Notch signaling during homeostasis, we demonstrate that satellite cells differentiate spontaneously and contribute to myofibers, thereby resulting in a severe depletion of the stem cell pool. Furthermore, whereas loss of Rbpj function provokes some satellite cells to proliferate before fusing, strikingly, the majority of mutant cells terminally differentiate unusually from the quiescent state, without passing through S‐phase. This study establishes Notch signaling pathway as the first regulator of cellular quiescence in adult muscle stem cells. STEM CELLS 2012; 30:243–252.
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.775