Galectin-3 Exerts a Pro-differentiating and Pro-myelinating Effect Within a Temporal Window Spanning Precursors and Pre-oligodendrocytes: Insights into the Mechanisms of Action

Abstract

Oligodendrocytes (OLG) are the cells resident in the CNS responsible for myelination. OLG undergo a succession of morphological and molecular changes along several maturational stages. Galectin-3 (Gal-3) is a 25- to 35-KDa protein belonging to the family of carbohydrate-binding galectins, which bind to glycoconjugates containing β-galactosides. Gal-3 lacks a specific receptor and its binding is thus rather unspecific, as it depends on the cellular environment and the repertoire of glycomolecules at the time when Gal-3 is present. Our previous work revealed that recombinant Gal-3 (rGal-3)–treated OLG showed accelerated differentiation, evidenced by an increase in the number of mature cells to the detriment of immature ones and accelerated actin cytoskeleton dynamics. These changes were a consequence of rGal-3 influence on Akt, Erk 1/2, and β-catenin signaling pathways. Considering this previous evidence, the aim of this study was to identify the temporal window of rGal-3 action on the OLG lineage to induce OLG maturation by using specific single pulses of rGal-3 over the different maturational stages of OLG, and to unravel its main direct targets promoting OLG differentiation by mass spectrometry analysis. Our results reveal a key temporal window spanning between OPC and pre-OLG states in which rGal-3 action promotes OLG differentiation, and identify several targets for rGal-3 binding including proteins related to the cytoskeleton, signaling pathways, metabolism and intracellular trafficking, among others. These results highlight the relevance of Gal-3 in signaling pathways regulating oligodendroglial differentiation and support a potential therapeutic role for rGal-3 in demyelinating diseases such as multiple sclerosis.