F3/Contactin Acts as a Functional Ligand for Notch during Oligodendrocyte Maturation

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.

Notch1 confers thymocytes a resistance to GC-induced apoptosis through Deltex1 by blocking the recruitment of p300 to the SRG3 promoter

“…It is possible that Deltex1 is preferred in binding to NotchIC to RBP-J, and the repressive effect through RBP-J may be minimal in the presence of Deltex1 at certain stages of differentiation and types of cells. 21,29 It has actually been reported that the expression of an excess amount of Deltex1 in COS-7 cells inhibited coprecipitation of RBP-J with NotchIC. 21 In addition, Deltex1 signaling is known to partially inhibit the Notch-mediated RBP-J signaling.…”

“…DN-Deltex1, containing amino acids 1-411 of Deltex1, is known to block homo-oligomerization of Deltex1 and, thus, act as a dominant-negative mutant. 21,29 The repression of the D2 luciferase reporter (Figure 4b), suggesting that this deletion mutant of Deltex1 has a dominant-negative function on the SRG3 promoter. NotchIC-mediated repression of the SRG3 promoter activity also was rescued by DN-Deltex1 in a dose-dependent manner (Figure 4b).…”

Discovery and initial verification of differentially abundant proteins between multiple sclerosis patients and controls using iTRAQ and SID-SRM

“…However, the two peptides used to monitor the abundance of contactin-1 did not show consistent significance between and within the different groups (Supplementary Table 6). Contactin-1 is a cell-adhesion glycoprotein distributed in the brain [49], and is highly involved in the regulation of oligodendrocyte survival, maturation, and myelination [50,51]. In the literature, increased abundance of contactin-1 have been verified in SPMS compared to controls using multiplex immunoassays [24], and decreased levels have also been found in multiple sclerosis compared to OND [30].…”

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

“…The canonical pathway through Jagged-Notch binding promotes the specification of oligodendrocyte-lineage cells from neural precursor cells while inhibiting their further differentiation into mature oligodendrocytes [33,34] . in MS, Jagged is re-expressed in astrocytes at the borders of active lesions [35] .…”