GALECTIN-3 DRIVES OLIGODENDROCYTE DIFFERENTIATION TO CONTROL MYELIN INTEGRITY AND FUNCTION

PASQUINI LAURA; MILLET VIOLETA; HOYOS HERNÁN; GIANNONI JUAN; CROCI DIEGO; LIU FU-TONG; RABINOVICH GABRIEL; PASQUINI JUANA

CELL DEATH AND DIFFERENTIATION

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2011 vol. 18 p. 1746 - 1756

1350-9047

Galectin-glycan lattices control critical pathophysiologic processes including the progression and resolution of 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 galectin-glycan interactions in the control of oligodendrocyte differentiation, myelin integrity and function. Both galectin-1 and -3 were abundant in astrocytes and microglia. While galectin-1 was abundant in immature but not in differentiated oligodendrocytes (OLG), galectin-3 was up-regulated during OLG differentiation. Biochemical analysis revealed increased activity of metalloproteinases responsible of 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 ‘glycosylation signature’ of immature versus differentiated OLG. Accordingly, conditioned medium from galectin-3-expressing, but not galectin-3-deficient (Lgals3-/-) 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 striatum of Lgals3-/- compared to wild type (WT) mice. Moreover, the myelin structure was loosely wrapped around the axons and less smooth in Lgals3-/- mice versus WT mice. Behaviour analysis revealed decreased anxiety in Lgals3-/- mice similar to that observed in early demyelination induced by cuprizone intoxication. Finally, commitment toward the oligodendroglial fate was favoured in neurospheres isolated from WT but not Lgals3-/- mice. Thus, 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.