title: Induction of Olig2 precursors by FGF involves BMP signalling blockade at the Smad level.
abstract: 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.
authors.affiliation: Department of Clinical Neurosciences and Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom. bb337@cam.ac.uk
authors.forename: Bilada
authors.initials: B
authors.lastname: Bilican
authors.forename: Christelle
authors.initials: C
authors.lastname: Fiore-Heriche
authors.forename: Alastair
authors.initials: A
authors.lastname: Compston
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Allen
authors.forename: Siddharthan
authors.initials: S
authors.lastname: Chandran
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D017931:DNA Primers; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000502:physiology*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000502:physiology*; D011401:Promoter Regions, Genetic; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000502:physiology*; D051898:Smad1 Protein / Q000502:physiology; D051901:Smad4 Protein / Q000502:physiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D007041:Hypoxanthine Phosphoribosyltransferase; D020929:Mitogen-Activated Protein Kinase Kinases; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D051785:Smad Proteins; D051898:Smad1 Protein; D051901:Smad4 Protein; C522729:Olig2 protein, rat; C497400:Smad1 protein, rat; C490811:Smad4 protein, rat