The protooncogene Ski controls Schwann cell proliferation and myelination.
Schwann cell proliferation and subsequent differentiation to nonmyelinating and myelinating cells are closely linked processes. Elucidating the molecular mechanisms that control these events is key to the understanding of nerve development, regeneration, nerve-sheath tumors, and neuropathies. We define the protooncogene Ski, an inhibitor of TGF-beta signaling, as an essential component of the machinery that controls Schwann cell proliferation and myelination. Functional Ski overexpression inhibits TGF-beta-mediated proliferation and prevents growth-arrested Schwann cells from reentering the cell cycle. Consistent with these findings, myelinating Schwann cells upregulate Ski during development and remyelination after injury. Myelination is blocked in myelin-competent cultures derived from Ski-deficient animals, and genes encoding myelin components are downregulated in Ski-deficient nerves. Conversely, overexpression of Ski in Schwann cells causes an upregulation of myelin-related genes. The myelination-regulating transcription factor Oct6 is involved in a complex modulatory relationship with Ski. We conclude that Ski is a crucial signal in Schwann cell development and myelination.
Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology, ETH-Hönggerberg, Zurich, Switzerland.
Suzana
S
Atanasoski
Lucia
L
Notterpek
Hye-Youn
HY
Lee
François
F
Castagner
Peter
P
Young
Markus U
MU
Ehrengruber
Dies
D
Meijer
Lukas
L
Sommer
Ed
E
Stavnezer
Clemencia
C
Colmenares
Ueli
U
Suter
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D011519:Proto-Oncogenes / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012583:Schwann Cells / Q000166:cytology* / Q000378:metabolism*; D012584:Sciatic Nerve / Q000166:cytology / Q000378:metabolism; D014162:Transfection
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C512653:Ski protein, mouse