F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation |
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Authors: | Hu Qi-Dong Ang Beng-Ti Karsak Meliha Hu Wei-Ping Cui Xiao-Ying Duka Tanya Takeda Yasuo Chia Wendy Sankar Natesan Ng Yee-Kong Ling Eng-Ang Maciag Thomas Small Deena Trifonova Radianna Kopan Raphael Okano Hideyuki Nakafuku Masato Chiba Shigeru Hirai Hisamaru Aster Jon C Schachner Melitta Pallen Catherine J Watanabe Kazutada Xiao Zhi-Cheng |
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Institution: | Department of Clinical Research, Singapore General Hospital, 169608, Singapore, Singapore. |
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Abstract: | 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. |
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