Regulation of oligodendrocyte progenitor cell maturation by PPARδ: effects on bone morphogenetic proteins

In EAE (experimental autoimmune encephalomyelitis), agonists of PPARs (peroxisome proliferator-activated receptors) provide clinical benefit and reduce damage. In contrast with PPARγ, agonists of PPARδ are more effective when given at later stages of EAE and increase myelin gene expression, suggesting effects on OL (oligodendrocyte) maturation. In the present study we examined effects of the PPARδ agonist GW0742 on OPCs (OL progenitor cells), and tested whether the effects involve modulation of BMPs (bone morphogenetic proteins). We show that effects of GW0742 are mediated through PPARδ since no amelioration of EAE clinical scores was observed in PPARδ-null mice. In OPCs derived from E13 mice (where E is embryonic day), GW0742, but not the PPARγ agonist pioglitazone, increased the number of myelin-producing OLs. This was due to activation of PPARδ since process formation was reduced in PPARδ-null compared with wild-type OPCs. In both OPCs and enriched astrocyte cultures, GW0742 increased noggin protein expression; however, noggin mRNA was only increased in astrocytes. In contrast, GW0742 reduced BMP2 and BMP4 mRNA levels in OPCs, with lesser effects in astrocytes. These findings demonstrate that PPARδ plays a role in OPC maturation, mediated, in part, by regulation of BMP and BMP antagonists

Induction of Olig2+ Precursors by FGF Involves BMP Signalling Blockade at the Smad Level

During normal development oligodendrocyte precursors (OPCs) are generated in the ventral spinal cord in response to Sonic hedgehog (Shh) signalling. There is also a second, late wave of oligodendrogenesis in the dorsal spinal cord independent of Shh activity. Two signalling pathways, controlled by bone morphogenetic protein and fibroblast growth factor (FGF), are active players in dorsal spinal cord specification. In particular, BMP signalling from the roof plate has a crucial role in setting up dorsal neural identity and its inhibition is sufficient to generate OPCs both in vitro and in vivo. In contrast, FGF signalling can induce OPC production from dorsal spinal cord cultures in vitro. In this study, we examined the cross-talk between mitogen-activated protein kinase (MAPK) and BMP signalling in embryonic dorsal spinal cord cultures at the SMAD1/5/8 (SMAD1) transcription factor level, the main effectors of BMP activity. We have previously shown that FGF2 treatment of neural precursor cells (NPCs) derived from rat E14 dorsal spinal cord is sufficient to generate OPCs in vitro. Utilising the same system, we now show that FGF prevents BMP-induced nuclear localisation of SMAD1-phosphorylated at the C-terminus (C-term-pSMAD1). This nuclear exclusion of C-term-pSMAD1 is dependent on MAPK activity and correlates with OLIG2 upregulation, the obligate transcription factor for oligodendrogenesis. Furthermore, inhibition of the MAPK pathway abolishes OLIG2 expression. We also show that SMAD4, which acts as a common partner for receptor-regulated Smads including SMAD1, associates with a Smad binding site in the Olig2 promoter and dissociates from it upon differentiation. Taken together, these results suggest that FGF can promote OPC generation from embryonic NPCs by counteracting BMP signalling at the Smad1 transcription factor level and that Smad-containing transcriptional complexes may be involved in direct regulation of the Olig2 promoter

Implication des Bone Morphogenetic Proteins dans le contrôle de la position des précurseurs oligodendrocytaires selon l'axe dorso-ventral de la moelle épinière embryonnaire chez le poulet

In the spinal cord, oligodendrocytes, the myelinating cells of the central nervous system, arise from the most ventral part of the neuroepithelium, reflecting the influence of Sonic Hedgehog (SHH), a morphogen secreted by the floor plate. Although the dorsal neuroepithelium does normally not generate oligodendrocytes, it can be induced to do so under certain conditions. This led us to test the idea that dorsal cues could locally inhibit oligodendrogenesis. In ovo removal of the dorsal most part of the spinal cord resulted in the specification of oligodendrocytes dorsal to their normal domain of emergence. Bone morphogenetic proteins (BMPs), expressed dorsally, invariably inhibited oligodendrocyte determination and expression of Olig2, a transcription factor required for this process, in vitro and in vivo, despite the presence of SHH. Thus, BMPs are among the dorsal signals that inhibit oligodendrocyte specification and contribute to the ventral restriction of initial steps of oligodendrogenesis by setting the dorsal border of the oligodendrogenic domain.Dans la moelle épinière, les oligodendrocytes, cellules myélinisantes du système nerveux central, dérivent de la région la plus ventrale du neuroépithélium, sous l'effet du morphogène Sonic Hedgehog (SHH) sécrété par la floor plate. Cependant, le neuroépithélium dorsal peut générer ces cellules dans certaines conditions. Pour expliquer l'absence d'oligodendrogenèse dorsale en situation normale, nous avons supposé l'existence de signaux inhibiteurs localement. L'ablation in ovo de la partie la plus dorsale de la moelle épinière entraîne, en effet, la spécification d'oligodendrocytes plus dorsaux. Les bone morphogenetic proteins (BMPs), exprimées dorsalement, inhibent la détermination des oligodendrocytes et l'expression du facteur de transcription Olig2, requis pour ce processus, malgré la présence de SHH in vitro et in vivo. Les BMPs font donc partie des signaux dorsaux inhibant la spécification des oligodendrocytes et fixent la limite dorsale du domaine oligodendrogénique

Implication des bone morphogenetic proteins dans le contrôle de la position des précurseurs oligodendrocytaires selon l'axe dorso-ventral de la moëlle épinière embryonnaire chez le poulet

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF