Teneurin-4 is a novel regulator of oligodendrocyte differentiation and myelination of small-diameter axons in the CNS.
Myelination is essential for proper functioning of the CNS. In this study, we have identified a mouse mutation, designated furue, which causes tremors and hypomyelination in the CNS, particularly in the spinal cord, but not in the sciatic nerve of the PNS. In the spinal cord of the furue mice, myelination of small-diameter axons was dramatically reduced, and differentiation of oligodendrocytes, the myelin-forming cells in the CNS, was inhibited. We subsequently found that the furue mutation was associated with a transgene insertion into the teneurin-4 (Ten-4, Ten-m4/Odz4) gene, encoding a transmembrane protein of unknown function. Ten-4 was strongly expressed in the spinal cord of wild-type mice and was induced during normal oligodendrocyte differentiation. In contrast, in the furue mice, the expression of Ten-4 was absent. Differentiation and cellular process formation of oligodendrocytes were inhibited in primary cell culture from the furue mice. Cell differentiation and process formation were also inhibited in the oligodendrocyte progenitor cell line CG-4 after suppression of Ten-4 expression by shRNA. Furthermore, Ten-4 positively regulated focal adhesion kinase, an essential signaling molecule for oligodendrocyte process formation and myelination of small-diameter axons. These findings suggest that Ten-4 is a novel regulator of oligodendrocyte differentiation and that it plays a critical role in the myelination of small-diameter axons in the CNS.
The Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20814, USA.
Nobuharu
N
Suzuki
Masaya
M
Fukushi
Keisuke
K
Kosaki
Andrew D
AD
Doyle
Susana
S
de Vega
Keigo
K
Yoshizaki
Chihiro
C
Akazawa
Eri
E
Arikawa-Hirasawa
Yoshihiko
Y
Yamada
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000941:Antigens / Q000378:metabolism; D001369:Axons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D001921:Brain / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics*; D048429:Cell Size; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003711:Demyelinating Diseases / Q000235:genetics*; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D005698:Galactosylceramidase / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D004676:Myelin Basic Protein / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D009836:Oligodendroglia / Q000166:cytology*; D038081:Organogenesis; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000099216:Chondroitin Sulfate Proteoglycan 4
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D025601:Adenomatous Polyposis Coli Protein; D000941:Antigens; D051417:Focal Adhesion Kinase 1; D005698:Galactosylceramidase; D008565:Membrane Proteins; D004676:Myelin Basic Protein; D009687:Nuclear Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015375:Receptors, Interleukin-2; D000099216:Chondroitin Sulfate Proteoglycan 4; C113761:Tenm4 protein, mouse; C496051:Ptk2 protein, mouse; C571338:Cnp protein, mouse