The cyclin-dependent kinase inhibitor p57kip2 is a negative regulator of Schwann cell differentiation and in vitro myelination.
The p57kip2 gene encodes a member of the cyclin-dependent kinase inhibitor family, proteins known to block G(1)/S transition during the mammalian cell cycle. We observed that expression of p57kip2 in Schwann cells of the developing and injured adult peripheral nervous system is dynamically regulated. Using gene knockdown by means of vector-based RNA interference in cultured primary Schwann cells we found that reduced levels of p57kip2 lead to cell cycle exit, actin filament stabilization, altered cell morphology and growth, and down-regulation of promyelinating markers as well as induction of myelin genes and proteins. In addition, we could demonstrate that in vitro myelination is enhanced by p57kip2-suppressed Schwann cells. Using microarray technology we found that these cellular reactions are specific to lowered p57kip2 expression levels and detected a shift of the transcriptional expression program toward the pattern known from Schwann cells in developing peripheral nerves. Because in the absence of axons primary Schwann cells normally do not display differentiation-associated reactions, we conclude that we have identified a mechanism and an important intrinsic negative regulator of myelinating glia differentiation.
Heinen
André
A
Department of Neurology, Heinrich Heine University, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
Kremer
David
D
Göttle
Peter
P
Kruse
Fabian
F
Hasse
Birgit
B
Lehmann
Helmar
H
Hartung
Hans Peter
HP
Küry
Patrick
P
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D002478:Cells, Cultured; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D009186:Myelin Sheath / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism*; D014162:Transfection
D050761:Cyclin-Dependent Kinase Inhibitor p57