Effect of Cytoskeletal Linker Protein GAS2L1 on Oligodendrocyte and Myelin Development.

Abstract

Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system (CNS), develop from OL precursor cells (OPCs) through a complex process involving significant morphological changes that are critically dependent on the dynamic interactions between cytoskeletal networks. Growth arrest-specific 2-like protein 1 (GAS2L1) is a cytoskeletal linker protein that mediates the cross-talk between actin filaments and microtubules. However, its role in OL and myelin development remains unknown. Here, we report that GAS2L1 is expressed in both OPCs and mature OLs, and that overexpression or knockdown of Gas2l1 in cultured OPCs in vitro impaired or enhanced their differentiation, respectively, while both inhibited their proliferation. We generated a Gas2l1^fl/fl mouse line and found that mice with conditional knockout of Gas2l1 in OL lineage cells (Olig1-Cre;Gas2l1^fl/fl, cKO) showed an increased number of mature OLs and enhanced myelination, as well as a reduction in the branching complexity of OPCs. In addition, an alternative mouse line with postnatally induced Gas2l1 ablation specifically in OPCs (Pdfgra-CreER^T2;Gas2l1^fl/fl, iKO) recapitulated the acceleration of OL and myelin development as well as the inhibition of OPC process branching. Furthermore, EdU tracking in Gas2l1 iKO mice in vivo and in their OPC cultures in vitro showed both a reduction in OPC proliferation and an increase in OL maturation. Finally, cultured OPCs from iKO mice showed an increase in filopodia extension. Taken together, our results demonstrate an effect of GAS2L1 on the regulation of OL/myelin development and may provide a novel potential therapeutic target for various diseases involving OL/myelin pathology.