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Dystroglycan regulates the Notch pathway to influence muscle stem cell maintenance
Author(s) -
Mizrachi Mark,
Wang Felix,
Sharma Himanshu,
Prives Joav,
Colognato Holly
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1063.4
Subject(s) - dystroglycan , notch signaling pathway , myod , microbiology and biotechnology , biology , stem cell , skeletal muscle , progenitor cell , notch proteins , myocyte , myogenesis , signal transduction , extracellular matrix , anatomy , laminin
The extracellular matrix receptor dystroglycan provides a critical structural linkage across the plasma membrane, bridging the extracellular matrix and cytoskeleton in skeletal muscle. Due to this key role, dystroglycan loss‐of‐function leads to membrane instability and muscle degeneration in a subset of muscular dystrophies termed dystroglycanopathies. However it is increasingly recognized that dysfunction in muscle stem cells, and the accompanying failed muscle regeneration, is also a critical factor in muscular dystrophy pathogenesis. Muscle stem cells rely upon Notch, a signaling receptor that regulates stem cell fate determination, to maintain the stem cell pool and to appropriately regulate muscle progenitor production and differentiation by regulating the expression of the transcription factors Pax7 and MyoD. We recently discovered that dystroglycan can suppress Notch signaling in neural stem cells to regulate neural progenitor cell production. We therefore hypothesized that dystroglycan may also regulate Notch signaling in muscle stem cells, termed satellite cells, during muscle regeneration. To test this hypothesis we used the C2C12 myoblast cell line as a model system for muscle satellite cells in which we could perturb dystroglycan expression or dystroglycan function, followed by an examination of Notch signaling and muscle stem and progenitor cell phenotypes. Our preliminary experiments indicate that dystroglycan does indeed regulate Notch signaling in muscle satellite cells although, surprisingly, dystroglycan appears to promote Notch signaling. Dystroglycan loss‐of‐function leads to decreased expression of canonical Notch target genes, decreased expression of Pax7, a transcription factor required for muscle stem cell maintenance, and precocious expression of MyoD, a transcription factor required for muscle cell differentiation. Together these data suggest a key role for dystroglycan in utilizing the Notch signaling pathway to regulate the balance between muscle stem cell and progenitor cell populations. These data further indicate that disturbances in Notch signaling and stem cell dysfunction may play a significant role in dystroglycanopathies and related muscular dystrophies. Support or Funding Information ASPET Summer Undergraduate Research Fellowship