While a role for YAP TAZ signaling in

While a role for YAP/TAZ signaling in oligodendrocytes has not been described, these nkh receptor are also responsive to mechanical stimuli. OPC proliferation and migration can be altered by plating on substrates of varying stiffness [20], resulting in differentiation in a density-dependent manner. Plating at high density with polystyrene beads promoted OPC differentiation, demonstrating that this process is mediated by physical space limitations, rather than by extracellular signals [21]. How might external forces drive oligodendrocyte development? A recent report demonstrates that mechanical stimuli interact with the nucleus via the Linker of Nucleoskeleton and Cytoskeleton complex (LINC). One LINC complex component in particular, SYNE1, which binds the nuclear envelope and actin, was shown to link extracellular stimuli, including high density plating with beads and mechanical force using a cell-compression device, to nuclear changes [22]. The switch from primarily euchromatin to heterochromatin is a hallmark of differentiation in oligodendrocytes [23] and requires SYNE1 []. Histone modifying complexes, specifically HDAC1 and HDAC2, affect nuclear reorganization by altering chromatin configuration and are essential for oligodendrocyte and SC differentiation. Epigenetic regulation of oligodendrocytes and SCs during development and myelination is reviewed in greater detail elsewhere [1, 4].
Producing the myelin sheath In a feat of cellular morphogenesis, glial cells massively upregulate production of their plasma membrane and spiral it around an axon segment. These dramatic shape changes require extensive cytoskeletal rearrangements, and great inroads have been made in understanding how such rearrangements drive myelin sheath formation. Using zebrafish in vivo imaging and 3D electron microscopic reconstruction, Snaidero and colleagues demonstrated that the plasma membrane inner tongue maintains contact with the axon segment as it wraps and progressively spreads out to form the myelin internode. Initial inner tongue movement is aided by the transport of critical material, including mRNA and protein, through cytoplasmic channels [24]. How is the inner tongue propelled around the axon? Two elegant studies suggest actin dynamics as a driving force. Nawaz et al. used zebrafish live imaging to determine that F-actin is initially localized to the leading edge, but later excluded from the developing membrane. Culture experiments demonstrated that F-actin depolymerization by drug treatment increased cell spreading, leading to a model in which the force of actin filament disassembly propels the membrane forward (Figure 2). Interestingly, Zuchero and colleagues found that actin disassembly is driven in part by competition of MBP protein for binding to PI(4,5)P2, which then releases the actin disassembly factors gelsolin and cofilin (Figure 2). The dynamic interplay between actin assembly during development and disassembly during myelination highlights a potential form of temporal control. Because actin assembly is necessary for OPC development [25], the timing of disassembly must be tightly regulated. What factors could influence timing? One possibility is axonal activity. In vitro, vesicular glutamate release from axons in response to electrical stimulation leads to phosphorylation of Fyn kinase at the oligodendrocyte membrane and local translation of Mbp [26]. Together, these discoveries implicate axons in temporally influencing myelination via actin disassembly. A role for actin dynamics has similarly been described in the PNS. Inhibition of F-actin formation resulted in delayed SC differentiation [27] and SC-specific deletion of neural Wiskott-Aldrich syndrome protein (N-WASp), a mechanical transducer that remodels actin via Arp2/3, inhibits myelination and causes motor deficits [28, 29]. Unlike oligodendrocytes, SCs must sort axons prior to myelination. Radial sorting, like myelination, requires dramatic cell shape changes that are mediated by proteins regulating the cytoskeleton, including the Rho family GTPases Rac1 and Cdc42 [30, 31]. Although these studies point to the importance of cytoskeletal rearrangements in SC development, less is known about the forces driving myelination. Interestingly, both oligodendrocytes and SCs transport Mbp along microtubules to sites of membrane elaboration [32, 33]. Whether actin disassembly and local translation of Mbp in SCs have roles in driving myelination remains to be determined.