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. 2016 Jun 8;9:33. doi: 10.3389/fnmol.2016.00033

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Copyright © 2016 Rao and Pearse.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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The involvement of Notch in the regulation of myelination and axonal growth. Myelinating glia (A) and the axonal membrane (B) both harbor notch ligands (C) and notch receptors (D). Proteases (e.g., ADAM10 and γ-secretase) activate the canonical notch signaling pathway (E) by processing the ligand bound notch receptor to release notch intracellular domain (NICD) (F). The protease ADAM 17 can activate canonical notch signaling in a ligand independent manner (G). NICD undergoes translocation to the nucleus and binds to a transcriptional de-repression complex containing RBPJ/MAML transcription factors (H1,H2). In myelinating glia, canonical notch signaling activates a cascade of downstream genes (e.g., Hes1), halting OPC differentiation (H1). Whereas, in neurons, canonical notch signaling upregulates DUSP1 and DUSP6 in a Hes/Hesr/Dec dependent manner (H2). DUSP1 and DUSP6 inhibit axonal growth and neuritogenesis by negatively regulating the p38 MAPK and ERK_1/2 pathways, respectively (I). Novel notch ligands (e.g., F3/contactin or NB3) activate non-canonical notch signaling (J) that recruits the NICD/Deltex1 (DTX1)/p300 transcription complex, thus activating genes that are essential for myelination. The notch antagonist, numb, inhibits various steps in both the canonical and non-canonical notch signaling pathway (K), whereas DTX1 plays a critical regulatory role in both non-canonical notch signaling and the c-Jun N-terminal kinase (JNK) signaling pathway (L).