Cell cycle inhibitors p21 and p16 are required for the regulation of Schwann cell proliferation.
Regulated cell proliferation is a crucial prerequisite for Schwann cells to achieve myelination in development and regeneration. In the present study, we have investigated the function of the cell cycle inhibitors p21 and p16 as potential regulators of Schwann cell proliferation, using p21- or p16-deficient mice. We report that both inhibitors are required for proper withdrawal of Schwann cells from the cell cycle during development and following injury. Postnatal Schwann cells express p21 exclusively in the cytoplasm, first detectable at postnatal day 7. This cytoplasmic p21 expression is necessary for proper Schwann cell proliferation control in the late development of peripheral nerves. After axonal damage, p21 is found in Schwann cell nuclei during the initiation of the proliferation period. This stage is critically regulated by p21, since loss of p21 leads to a strong increase in Schwann cell proliferation. Unexpectedly, p21 levels are upregulated in this phase suggesting that the role of p21 may be more complex than purely inhibitory for the Schwann cell cycle. However, inhibition of Schwann cell proliferation is the overriding crucial function of p21 and p16 in peripheral nerves as revealed by the consequences of loss-of-function in development and after injury. Different mechanisms appear to underlie the inhibitory function, depending on whether p21 is cytoplasmic or nuclear.
Atanasoski
Suzana
S
Department of Biology, Institute of Cell Biology, Swiss Federal Institute of Technology, ETH-Hönggerberg, Zurich, Switzerland.
Boller
Danielle
D
De Ventura
Lukas
L
Koegel
Heidi
H
Boentert
Matthias
M
Young
Peter
P
Werner
Sabine
S
Suter
Ueli
U
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors; D007124:Immunoenzyme Techniques; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009412:Nerve Fibers / Q000502:physiology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000187:drug effects*; D012584:Sciatic Nerve / Q000293:injuries; D012867:Skin / Q000293:injuries / Q000473:pathology; D014162:Transfection; D014945:Wound Healing
D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21