F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation.
Axon-derived molecules are temporally and spatially required as positive or negative signals to coordinate oligodendrocyte differentiation. Increasing evidence suggests that, in addition to the inhibitory Jagged1/Notch1 signaling cascade, other pathways act via Notch to mediate oligodendrocyte differentiation. The GPI-linked neural cell recognition molecule F3/contactin is clustered during development at the paranodal region, a vital site for axoglial interaction. Here, we show that F3/contactin acts as a functional ligand of Notch. This trans-extracellular interaction triggers gamma-secretase-dependent nuclear translocation of the Notch intracellular domain. F3/Notch signaling promotes oligodendrocyte precursor cell differentiation and upregulates the myelin-related protein MAG in OLN-93 cells. This can be blocked by dominant negative Notch1, Notch2, and two Deltex1 mutants lacking the RING-H2 finger motif, but not by dominant-negative RBP-J or Hes1 antisense oligonucleotides. Expression of constitutively active Notch1 or Notch2 does not upregulate MAG. Thus, F3/contactin specifically initiates a Notch/Deltex1 signaling pathway that promotes oligodendrocyte maturation and myelination.
Department of Clinical Research, Singapore General Hospital, 169608, Singapore, Singapore.
Qi-Dong
QD
Hu
Beng-Ti
BT
Ang
Meliha
M
Karsak
Wei-Ping
WP
Hu
Xiao-Ying
XY
Cui
Tanya
T
Duka
Yasuo
Y
Takeda
Wendy
W
Chia
Natesan
N
Sankar
Yee-Kong
YK
Ng
Eng-Ang
EA
Ling
Thomas
T
Maciag
Deena
D
Small
Radianna
R
Trifonova
Raphael
R
Kopan
Hideyuki
H
Okano
Masato
M
Nakafuku
Shigeru
S
Chiba
Hisamaru
H
Hirai
Jon C
JC
Aster
Melitta
M
Schachner
Catherine J
CJ
Pallen
Kazutada
K
Watanabe
Zhi-Cheng
ZC
Xiao
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D016466:CHO Cells; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation; D018920:Coculture Techniques; D058966:Contactins; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000502:physiology*; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D015816:Cell Adhesion Molecules, Neuronal; D058966:Contactins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D008024:Ligands; D008565:Membrane Proteins; D018992:Myelin-Associated Glycoprotein; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D000072056:Transcription Factor HES-1; D044767:Ubiquitin-Protein Ligases; C489734:Hes1 protein, mouse; C489735:Hes1 protein, rat; C078493:HES1 protein, human; C104035:Dtx1 protein, mouse