Evolvability of the actin cytoskeleton in oligodendrocytes during central nervous system development and aging

Abstract

The organization of actin filaments into a wide range of subcellular structures is a defining feature of cell shape and dynamics, important for tissue development and homeostasis. Nervous system function requires morphological and functional plasticity of neurons and glial cells, which is largely determined by the dynamic reorganization of the actin cytoskeleton in response to intrinsic and extracellular signals. Oligodendrocytes are specialized glia that extend multiple actin-based protrusions to form the multilayered myelin membrane that spirally wraps around axons, increasing conduction speed and promoting long-term axonal integrity. Myelination is a remarkable biological paradigm in development, and maintenance of myelin is essential for a healthy adult nervous system. In this review, we discuss how structure and dynamics of the actin cytoskeleton is a defining feature of myelinating oligodendrocytes' biology and function. We also review "old and new" concepts to reflect on the potential role of the cytoskeleton in balancing life and death of myelin membranes and oligodendrocytes in the aging central nervous system.

Keywords: Age-associated cognitive decline; Brain aging; Cellular aging; Glia; Membrane remodeling; Myelin; White matter.

Fig. 1

The evolution of actin filament dynamics and expression of actin-binding proteins during oligodendrocyte differentiation and myelination. a Abundance of transcripts encoding proteins that regulate actin dynamics in distinct oligodendrocyte differentiation states. Molecules were grouped into four functional classes according to their effect on actin filament dynamics and/or organization. mRNA expression levels were obtained from http://www.brainrnaseq.org [26]. b Cartoon depicting the predominant actin network structures tied to each developmental stage of oligodendrocyte differentiation. In OPCs, actin filament polymerization and elongation by, for example, formins and the Arp2/3 complex are favored. The second highest represented class of actin-binding proteins in OPCs are crosslinkers and anchoring elements such as filamin, dystrophin and ERM (ezrin, radixin, and moesin) proteins. In newly-formed oligodendrocytes, assembly and elongation of actin filaments predominates, together with an increased abundance of bundling elements (such as coronins and fascin). High expression of filament depolymerizing (e.g., cofilin), severing (e.g., gelsolin), and capping (e.g., capZ) factors greatly favors actin filament disassembly and stabilization in myelinating oligodendrocytes. The second highest represented classes of actin-binding proteins in myelinating oligodendrocytes are crosslinkers (e.g., septins) and bundlers (e.g., anillin and ermin). c F-actin localization in live cultured oligodendrocytes during differentiation (image stills from time lapse microscopy videos [8]). d, e Schematic representation of the morphological transformation-from high protrusion remodeling to membrane-forming oligodendrocytes-characteristic of differentiation in vitro and myelination in vivo, respectively