N-Wasp Regulates Oligodendrocyte Myelination

Abstract

Oligodendrocyte myelination depends on actin cytoskeleton rearrangement. Neural Wiskott-Aldrich syndrome protein (N-Wasp) is an actin nucleation factor that promotes polymerization of branched actin filaments. N-Wasp activity is essential for myelin membrane wrapping by Schwann cells, but its role in oligodendrocytes and CNS myelination remains unknown.Here we report that oligodendrocytes-specific deletion of N-Wasp in mice of both sexes resulted in hypomyelination (i.e., reduced number of myelinated axons and thinner myelin profiles), as well as substantial focal hypermyelination reflected by the formation of remarkably long myelin outfolds. These myelin outfolds surrounded unmyelinated axons, neuronal cell bodies, and other myelin profiles. The latter configuration resulted in pseudo-multimyelin profiles that were often associated with axonal detachment and degeneration throughout the CNS, including in the optic nerve, corpus callosum, and the spinal cord. Furthermore, developmental analysis revealed that myelin abnormalities were already observed during the onset of myelination, suggesting that they are formed by aberrant and misguided elongation of the oligodendrocyte inner lip membrane. Our results demonstrate that N-Wasp is required for the formation of normal myelin in the CNS. They also reveal that N-Wasp plays a distinct role in oligodendrocytes compared with Schwann cells, highlighting a difference in the regulation of actin dynamics during CNS and PNS myelination.

Pinch2 is a novel regulator of myelination in the Central Nervous System

“…Myelin outfoldings occur during normal development (Patzig et al, 2016, Snaidero et al, 2014) and are also a hallmark of age-dependent pathology in the CNS (Peters, 2002). In the mature CNS, an increased frequency of myelin outfoldings has been observed upon experimentally increasing PIP3 levels (Goebbels et al, 2010), changing actin organization and dynamics (Zuchero et al, 2015, Katanov et al, 2020) and septin assembly (Patzig et al, 2016; Erwig et al, 2019). Pinch2 cKO-in which we observed a reduction in the pool of active Cdc42 (and Rac1, not shown)-displayed myelin outfoldings similar to those previously reported for OL- Cdc42 / Rac1 conditional knockouts (Thurnherr et al, 2006).…”

SKAP2 as a new regulator of oligodendroglial migration and myelin sheath formation

“…Interestingly, the mTOR regulated proteome includes also FYN (Tyler et al, 2011) providing a potential link to upstream activation of SKAP2. Moreover, a signaling network involving N‐WASP as key regulator of ARP2/3‐driven actin polymerization and myelination has been described indicating another possible mechanism involving SKAP2 as adaptor (Katanov et al, 2020). Taken together, we hypothesize that SKAP2 is most important during phases of highest actin turnover and functions as adaptor protein, which associates with either F‐actin directly mediating its stability or different binding partners modulating actin polymerization and depolymerization, respectively (Figure 6).…”

New Species Can Broaden Myelin Research: Suitability of Little Skate, Leucoraja erinacea

“…They are rarely observed in healthy adult mammalian CNS nor in spinal cords of mature spiny dogfish [ 27 ] and little skate (unpublished observations). They are far more commonly associated with the myelin sheaths of mice formed under compromised conditions, i.e., the absence of myelin-associated glycoprotein [ 71 ], the absence of 2’,3’-cyclic nucleotide 3’-phosphodiesterase [ 72 ], the absence of PLP [ 73 ] and/or diminished anillin/septin scaffolds [ 73 , 74 ], myotubularin 2-related protein [ 75 ], as well as actin bundling-related structures [ 76 ]. One possible explanation for their presences in developing little skate spinal cord, optic and spinal nerves is that the myelin outfoldings, apparently more frequent and larger in smaller fibers, are due to an abundant production in outlying portions of internodes that are used to accommodate myelin membrane expansion around the axons as they enlarge in caliber and length.…”