Interaction of fibroblast growth factor 2 (FGF2) and notch signaling components in inhibition of oligodendrocyte progenitor (OP) differentiation

Abstract

Oligodendrocyte progenitor (OP) cell differentiation is a critical process of developmental myelination, tumor formation, and remyelination in the CNS. Activation of the fibroblast growth factor 2 (FGF2) or notch pathway can inhibit differentiation of OP cells. The current study examines the interaction of FGF2 and notch signaling components in regulating OP differentiation. Cultured neonatal rat brain OP cells were used for transfection-based promoter assays and for infection with retroviruses expressing a GFP reporter to monitor OP differentiation into oligodendrocytes or astrocytes. FGF2 treatment resulted in a 4-fold increase of transcriptional activity from the promoter region of Hes5, a notch pathway target gene. FGF2 inhibition of OP differentiation into oligodendrocytes was perturbed by retroviral expression of a dominant negative construct for mastermind-like 1, which is an important co-activator of transcription for notch target genes. OP differentiation into oligodendrocytes was reduced by co-culture with fibroblasts expressing Jagged1, a ligand for notch receptors. This Jagged1 inhibition of OP differentiation was not altered by retroviral expression of a dominant negative FGF receptor construct. Constitutive activation of notch signaling, by retroviral expression of the Notch1 intracellular domain, greatly reduced OP differentiation into either oligodendrocytes or astrocytes and did not require FGF2 signaling. These findings indicate that inhibition of OP differentiation through the Notch1 pathway was not influenced by FGF2 signaling. However, FGF2 signaling may interact with down stream components of the notch signaling pathway, including mastermind-like1 and Hes5, to inhibit OP differentiation into oligodendrocytes.

Notch signaling augments the canonical Wnt pathway to specify the size of the otic placode

“…2B, Fig. 7), whereas Notch1 and Hes1 expression might be initiated by Wnt signaling, and possibly also by FGFs (Norgaard et al, 2003;Zhou and Armstrong, 2007), in addition to by Notch signaling itself. …”

“…2B, Fig. 7), whereas Notch1 and Hes1 expression might be initiated by Wnt signaling, and possibly also by FGFs (Norgaard et al, 2003;Zhou and Armstrong, 2007), in addition to by Notch signaling itself. Jag1-Notch1 signaling augments Wnt signals in the medial region of the otic placode, whereas more lateral regions are not exposed to Notch1 signals and Wnt signaling is not augmented.…”

Mechanostimulation Promotes Nuclear and Epigenetic Changes in Oligodendrocytes

“…It has been recently shown that F-actin depolymerization is critical for myelination and necessary for the formation of myelin wraps along the axons in the CNS (Nawaz et al, 2015;Zuchero et al, 2015). However, the concept of G-actin-mediated modulation of a transcriptional program accompanying oligodendrocyte morphological changes has not been reported.…”

“…Myelinating oligodendrocytes differentiate in response to soluble chemical signals (Hart et al, 1989;Barres et al, 1994;Gao et al, 1998;Pombo et al, 1999;Lu et al, 2000;Nery et al, 2001;Samanta and Kessler, 2004;Fortin et al, 2005;Zhou and Armstrong, 2007;Furusho et al, 2011;Dugas et al, 2012;Wu et al, 2012) as well as physical perturbations (Rosenberg et al, 2008;Jagielska et al, 2012), but the pathways connecting spatial constraints to transcriptional changes have not been identified. Previous work on epigenetics of developmental myelination highlighted the importance of heterochromatin formation during oligodendrocyte differentiation (Marin-Husstege et al, 2002;Ye et al, 2009;Magri et al, 2014;Liu et al, 2015), with an emphasis on histone deacetylation and repressive trimethylation of lysine residues (Marin-Husstege et al, 2002;Shen et al, 2005;Ye et al, 2009;Liu and Casaccia, 2010;Sher et al, 2012;Liu et al, 2015).…”

Extracellular cues influencing oligodendrocyte differentiation and (re)myelination

“…Effects described for FGF-2 on terminally differentiated OLGs include a downregulation of myelin gene expression, re-entry into the cell cycle and a loss of membrane sheath formation mediated by FGFR1, as well as a stimulation of process elongation via FGFR3 (Bansal and Pfeiffer, 1997; Fortin et al, 2005; Fressinaud et al, 1995, 1993; Grinspan et al, 1993, 1996; Hoffman and Duncan, 1995; Muir and Compston, 1996; Wang et al, 2007; Zhou et al, 2006). Interestingly, the OLG differentiation inhibitory effects of FGF-2 signaling have been proposed to include an interaction with downstream targets of the Notch pathway, including an upregulation of Hes5 expression (Zhou and Armstrong, 2007). Consistent with the above in vitro described effects of FGF-2 on OLG differentiation, transgenic mice expressing a dominant-negative FGFR1, under the control of the myelin basic protein (MBP) promoter, showed an increase in myelin thickness (Harari et al, 1997).…”