Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination

Abstract

A requisite component of nervous system development is the achievement of cellular recognition and spatial segregation through competition-based refinement mechanisms. Competition for available axon space by myelinating oligodendrocytes ensures that all relevant CNS axons are myelinated properly. To ascertain the nature of this competition, we generated a transgenic mouse with sparsely labeled oligodendrocytes and establish that individual oligodendrocytes occupying similar axon tracts can greatly vary the number and lengths of their myelin internodes. Here we show that intercellular interactions between competing oligodendroglia influence the number and length of myelin internodes, referred to as myelinogenic potential, and identify the amino-terminal region of Nogo-A, expressed by oligodendroglia, as necessary and sufficient to inhibit this process. Exuberant and expansive myelination/ remyelination is detected in the absence of Nogo during development and after demyelination, suggesting that spatial segregation and myelin extent is limited by microenvironmental inhibition. We demonstrate a unique physiological role for Nogo-A in the precise myelination of the developing CNS. Maximizing the myelinogenic potential of oligodendrocytes may offer an effective strategy for repair in future therapies for demyelination.T he spatial alignment of myelin internodes along axons facilitates the process of saltatory conduction, maximizing the speed and efficacy of action potential propagation throughout the nervous system. In the CNS, myelin is formed by oligodendrocytes, cells with the capacity to form multiple myelin internodes (1). What developmental mechanisms control the generation and coordination of the precise number and length of myelin internodes? Though recent studies have revealed extrinsic cues and transcriptional and epigenetic determinants that regulate oligodendrocyte differentiation (2-7), achievement of the precise spatial organization of myelin internodes necessitates a mechanism whereby neighboring oligodendroglial cells coordinate the appropriate number of myelin internodes generated. This coordination could be achieved through oligodendroglial competition for inductive cues and/or available axonal space (8). Variations in the number and length of myelin internodes formed by individual oligodendrocytes support the likelihood of environmental regulation of myelination. However, providing evidence of this variation requires a strategy that facilitates the resolution and analysis of individual myelinating oligodendrocytes in vivo. Results Individual Oligodendrocytes Exhibit Great Variability in the Numberand Lengths of Myelin Internodes Throughout the CNS. Though the heterogeneity of oligodendrocyte morphology has been recognized for the past century (9, 10), efforts to accurately examine oligodendrocytes have been hindered by the high density of myelinating cells, limiting the ability to confidently attribute specific myelin internodes to any particular oligodendrocyte. Existing methods approximate the n...

Myelination and mTOR

“…The following average dimensions have been considered: Myelinating SCs in the rat sciatic nerve wrap their membrane 72–94 times around axons and outstretch 650‐μm long internodes on average (Webster, 1971); myelinating OLs in the rat optic nerve wrap up to 30 times, extend on average 200‐μm long internodes (Butt & Ransom, 1993; Wiggins, Fuller, Brizzee, Bissel, & Samorajski, 1984), and myelinate on average 16 axons (Butt & Ransom, 1993). Of note, although no data are available for rat OLs, variations in the length of the internodes myelinated by a single OL have been reported in mice (Chong et al, 2012). For SCs and OLs, the total surface area of myelinating cells has been estimated, on average, to 20 × 10 5 μm 2 (Pfeiffer, Warrington, & Bansal, 1993; Webster, 1971)…”

Oligodendrocytes: Myelination and Axonal Support

“…Most oligodendrocytes generate between 20 and 60 myelinating processes with intermodal lengths of 20 mm -200 mm and up to 100 membrane turns (Matthews and Duncan 1971;Hildebrand et al 1993;Chong et al 2012). When estimating the "surface" area that one oligodendrocyte would have (in terms of myelin membrane), it sums up to 5-50 Â 10 3 mm 2 , a number not reached by any other cell in our body (Pfeiffer et al 1993;Baron and Hoekstra 2010).…”

Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice

“…For instance, Notch/delta/jagged signaling, extracellular matrix (ECM)-associated hyaluronan sulfate proteoglycans (HSPGs), chondroitin sulfate proteoglycans (CPSGs), Semaphorin 3A, canonical Wnt, and Nogo/NgR1 signaling are some of the candidate systems that may contribute to such an outcome (28)(29)(30). Among these, Nogo/NgR1 signaling plays a central role in the differentiation and integration of OPCs (31). NgR1 was originally described as the Nogo receptor 1 for myelin-associated ligands (Nogo, MAG, and OMgp) in axonal growth inhibition, but recent evidence indicates that NgR1 can bind to many molecules in the ECM, including many of the myelin and ECM molecules that modulate OPC differentiation (32).…”