32 research outputs found
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
Galectin-3 drives oligodendrocyte differentiation to control myelin integrity and function
Galectins control critical pathophysiological processes, including the progression and resolution of central nervous system (CNS) inflammation. In spite of considerable progress in dissecting their role within lymphoid organs, their functions within the inflamed CNS remain elusive. Here, we investigated the role of galectinâglycan interactions in the control of oligodendrocyte (OLG) differentiation, myelin integrity and function. Both galectin-1 and -3 were abundant in astrocytes and microglia. Although galectin-1 was abundant in immature but not in differentiated OLGs, galectin-3 was upregulated during OLG differentiation. Biochemical analysis revealed increased activity of metalloproteinases responsible for cleaving galectin-3 during OLG differentiation and modulating its biological activity. Exposure to galectin-3 promoted OLG differentiation in a dose- and carbohydrate-dependent fashion consistent with the âglycosylation signatureâ of immature versus differentiated OLG. Accordingly, conditioned media from galectin-3-expressing, but not galectin-3-deficient (Lgals3â/â) microglia, successfully promoted OLG differentiation. Supporting these findings, morphometric analysis showed a significant decrease in the frequency of myelinated axons, myelin turns (lamellae) and g-ratio in the corpus callosum and striatum of Lgals3â/â compared with wild-type (WT) mice. Moreover, the myelin structure was loosely wrapped around the axons and less smooth in Lgals3â/â mice versus WT mice. Behavior analysis revealed decreased anxiety in Lgals3â/â mice similar to that observed during early demyelination induced by cuprizone intoxication. Finally, commitment toward the oligodendroglial fate was favored in neurospheres isolated from WT but not Lgals3â/â mice. Hence, glial-derived galectin-3, but not galectin-1, promotes OLG differentiation, thus contributing to myelin integrity and function with critical implications in the recovery of inflammatory demyelinating disorders.Fil: Pasquini, Laura Andrea. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de QuĂmica y FĂsico-QuĂmica BiolĂłgicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y BioquĂmica. Instituto de QuĂmica y FĂsico-QuĂmica BiolĂłgicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂmica. Departamento de QuĂmica BiolĂłgica; ArgentinaFil: Millet, Violeta. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂmica. Departamento de QuĂmica BiolĂłgica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de QuĂmica y FĂsico-QuĂmica BiolĂłgicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y BioquĂmica. Instituto de QuĂmica y FĂsico-QuĂmica BiolĂłgicas; ArgentinaFil: Hoyos, HernĂĄn Carlos. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂmica. Departamento de QuĂmica BiolĂłgica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de QuĂmica y FĂsico-QuĂmica BiolĂłgicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y BioquĂmica. Instituto de QuĂmica y FĂsico-QuĂmica BiolĂłgicas; ArgentinaFil: Giannoni, J. P.. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂmica. Departamento de QuĂmica BiolĂłgica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de QuĂmica y FĂsico-QuĂmica BiolĂłgicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y BioquĂmica. Instituto de QuĂmica y FĂsico-QuĂmica BiolĂłgicas; ArgentinaFil: Croci Russo, Diego Omar. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de BiologĂa y Medicina Experimental. FundaciĂłn de Instituto de BiologĂa y Medicina Experimental. Instituto de BiologĂa y Medicina Experimental; ArgentinaFil: Marder, Nora Mariel. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂmica. Departamento de QuĂmica BiolĂłgica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de QuĂmica y FĂsico-QuĂmica BiolĂłgicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y BioquĂmica. Instituto de QuĂmica y FĂsico-QuĂmica BiolĂłgicas; ArgentinaFil: Liu, F. T.. University of California at Davis; Estados UnidosFil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de BiologĂa y Medicina Experimental. FundaciĂłn de Instituto de BiologĂa y Medicina Experimental. Instituto de BiologĂa y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de QuĂmica BiolĂłgica; ArgentinaFil: Pasquini, Juana Maria. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂmica. Departamento de QuĂmica BiolĂłgica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de QuĂmica y FĂsico-QuĂmica BiolĂłgicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y BioquĂmica. Instituto de QuĂmica y FĂsico-QuĂmica BiolĂłgicas; Argentin