Abstract
Many types of progenitor cells are distinguished by the expression of
the intermediate filament protein nestin, a frequently used stem cell
marker, the physiological roles of which are still unknown. Whereas
myogenesis is characterized by dynamically regulated nestin levels, we
studied how altering nestin levels affects myoblast differentiation.
Nestin determined both the onset and pace of differentiation. Whereas
depletion of nestin by RNAi strikingly accelerated the process,
overexpression of nestin completely inhibited differentiation. Nestin
down-regulation augmented the early stages of differentiation, at the
level of cell-cycle withdrawal and expression of myogenic markers, but
did not affect proliferation of undifferentiated dividing myoblasts.
Nestin regulated the cleavage of the Cdk5 activator protein p35 to its
degradation-resistant form, p25. In this way, nestin has the capacity to
halt myoblast differentiation by inhibiting sustained activation of
Cdk5 by p25, which is critical for the progress of differentiation. Our
results imply that nestin regulates the early stages of myogenesis
rather than maintains the undifferentiated state of progenitor cells. In
the bidirectional interrelationship between nestin and Cdk5, Cdk5
regulates the organization and stability of its own nestin scaffold,
which in turn controls the effects of Cdk5. This nestin–Cdk5 cross-talk
sets the pace of muscle differentiation.
Original language | English |
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Pages (from-to) | 1539-1549 |
Journal | Molecular Biology of the Cell |
Volume | 22 |
Issue number | 9 |
DOIs | |
Publication status | Published - 2011 |
MoE publication type | A1 Journal article-refereed |
Keywords
- intermediate filaments
- nestin
- Cdk5 signaling
- p35
- muscle differentiation