Postnatal Schwann cell proliferation but not myelination is strictly and uniquely dependent on cyclin-dependent kinase 4 (cdk4).
Peripheral myelin formation depends on axonal signals that tightly control proliferation and differentiation of the associated Schwann cells. Here we demonstrate that the molecular program controlling proliferation of Schwann cells switches at birth. We have analyzed the requirements for three members of the cyclin-dependent kinase (cdk) family in Schwann cells using cdk-deficient mice. Mice lacking cdk4 showed a drastic decrease in the proliferation rate of Schwann cells at postnatal days 2 and 5, but proliferation was unaffected at embryonic day 18. In contrast, ablation of cdk2 and cdk6 had no significant influence on postnatal Schwann cell proliferation. Taken together, these findings indicate that postnatal Schwann cell proliferation is uniquely controlled by cdk4. Despite the lack of the postnatal wave of Schwann cell proliferation, axons were normally myelinated in adult cdk4-deficient sciatic nerves. Following nerve injury, Schwann cells lacking cdk4 were unable to re-enter the cell cycle, while Schwann cells deficient in cdk2 or cdk6 displayed proliferation rates comparable to controls. We did not observe compensatory effects such as elevated cdk4 levels in uninjured or injured nerves of cdk2 or cdk6-deficient mice. Our data demonstrate that prenatal and postnatal Schwann cell proliferation are driven by distinct molecular cues, and that postnatal proliferation is not a prerequisite for the generation of Schwann cell numbers adequate for correct myelination.
Atanasoski
Suzana
S
Institute of Cell Biology, ETH Zurich, Zurich, Switzerland. suzana.atanasoski@unibas.ch
Boentert
Matthias
M
De Ventura
Lukas
L
Pohl
Hartmut
H
Baranek
Constanze
C
Beier
Konstantin
K
Young
Peter
P
Barbacid
Mariano
M
Suter
Ueli
U
D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000172:deficiency; D051358:Cyclin-Dependent Kinase 4 / Q000172:deficiency / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000172:deficiency; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism*; D051381:Rats; D012583:Schwann Cells / Q000502:physiology*; D020426:Sciatic Neuropathy / Q000201:enzymology*; D014855:Wallerian Degeneration / Q000378:metabolism
D019394:Ki-67 Antigen; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D001973:Bromodeoxyuridine