Revisiting Notch in remyelination of multiple sclerosis lesions
Celia F. Brosnan, Gareth R. John
Celia F. Brosnan, Gareth R. John
Published December 22, 2008
Citation Information: J Clin Invest. 2009;119(1):10-13. https://doi.org/10.1172/JCI37786.
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Commentary

Revisiting Notch in remyelination of multiple sclerosis lesions

Abstract

MS results from destruction of the protective myelin sheath surrounding axons, which prevents the transmission of nerve impulses. Precursors of oligodendrocytes, the cells capable of myelinating axons, are preserved in demyelinating lesions; however, why these precursors do not differentiate into mature oligodendrocytes and remyelinate axons is unknown. Contactin is a noncanonical Notch receptor ligand that mediates oligodendrocyte differentiation. In this issue of the JCI, Nakahara et al. show that Contactin is abundantly expressed on demyelinated axons in human chronic MS lesions and that Notch1 is activated in oligodendrocyte precursor cells (see the related article beginning on page 169). However, Notch1 intracellular domain coassociates with the nuclear transporter Importin β but fails to show evidence of nuclear translocation. These cytoplasmic aggregates also contain TAT-interacting protein 30 kDa (TIP30), a proapoptotic factor, which inhibits nuclear transport and, consequently, Notch1-mediated oligodendrocyte differentiation and remyelination. These data target TIP30 as a new pathogenic factor in MS.

Authors

Celia F. Brosnan, Gareth R. John

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Figure 1

Notch1 ligands differentially regulate OPC development.

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Notch1 ligands differentially regulate OPC development. The figure depic...
The figure depicts the outcome of the interaction of different ligands with the Notch1 receptor, which triggers signaling via two distinct pathways. Canonical ligands of the DSL family activate genes such as HES1 and HES5 (HES1,5) that inhibit OPC differentiation but permit OPC proliferation, resulting in the maintenance and/or expansion of the OPC pool. In contrast, the noncanonical ligand F3/Contactin leads to OPC differentiation and subsequent myelination of axons by promoting expression of myelin genes such as myelin-associated glycoprotein (MAG). However, in this issue of the JCI, Nakahara et al. (8) present data supporting the conclusion that in MS lesions, activation of the noncanonical pathway may fail due to pathologic upregulation of TIP30, a protein that blocks nuclear transport of NICD. NICD entrapment in the cytoplasm prevents OPC differentiation and axon myelination (see schematic representation depicted in Figure 9 of the Nakahara et al. study; ref. 8).