title: Nestin as a regulator of Cdk5 in differentiating myoblasts.
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.
authors.affiliation: Turku Center for Biotechnology, University of Turku and Åbo Akademi University, FIN-20521, Turku, Finland.
authors.forename: Hanna-Mari
authors.initials: HM
authors.lastname: Pallari
authors.forename: Julia
authors.initials: J
authors.lastname: Lindqvist
authors.forename: Elin
authors.initials: E
authors.lastname: Torvaldson
authors.forename: Saima E
authors.initials: SE
authors.lastname: Ferraris
authors.forename: Tao
authors.initials: T
authors.lastname: He
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sahlgren
authors.forename: John E
authors.initials: JE
authors.lastname: Eriksson
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D024510:Muscle Development / Q000235:genetics; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D064231:Nestin; D010770:Phosphotransferases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: C492236:Cdk5r1 protein, mouse; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D034741:RNA, Small Interfering; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5