The formation of the myelin sheath is a highly complex process that involves a number of steps, from mRNA transcription to protein translation and assembly into the membranes. All of the myelin products have to be transported from the cell body and targeted to the 'workface' of the myelin sheath, over hundreds and potentially thousands of microns via the connecting branches (in oligodendrocytes), and along the outer cytoplasmic ridge, down the paranodal loops, into the inner cytoplasmic ridge and Schmidt-Lanterman incisures. Lipids are probably targeted to the myelin sheath by associations with proteins, and lipid rafts provide a mechanism by which lipids and proteins are delivered to growing membrane. However, movement over hundreds of microns is achieved by intracellular transport involving microtubules and other components of the cytoskeleton, which are similar in oligodendrocytes and Schwann cells. One of the most interesting aspects of protein targeting in myelinating cells is the phenomenon of MBP mRNA translocation from the cell body to the myelin sheaths. The MBPs are highly cationic polypeptides that interact with virtually any negatively charged molecule. Consequently, MBP is not translated in the cell body, where its interactions with other cellular components would impede its transport to the myelin sheath. Instead, the MBP mRNA is translocated in ribonucleoprotein granules along microtubules to the distal cytoplasmic ridges of the myelin sheath, where the protein is translated 'on site'. PLP and the other main proteins are translated within the cell body and the protein is transported to the distal myelin sheath. Hence, in situ hybridization clearly shows MBP mRNA in the cell body, processes and myelin sheaths of oligodendrocytes, whereas PLP mRNA is localized to the cell body. In contrast, immunostaining for the proteins shows MBP localized within the myelin sheath and PLP within the cell body, processes and myelin sheath. In all cases, transport is along microtubules. Translocated MBP mRNA contains an A2RE element that binds the hnRNP A2 protein, and the mRNA granule-hnRNP A2 protein complex is transported along microtubules in the processes, dependent on the microtubule associated protein (MAP) TOG2. The two major MAPs in oligodendrocytes, MAP2 and tau, regulate microtubule assembly and are critical for oligodendrocyte differentiation and myelination. The importance of micro-tubules is demonstrated in the taiep rat, where microtubular dysfunction results in the accumulation of MBP mRNA and myelin proteins in the cell bodies and dysmyelination. In addition, oligodendrocytes are disrupted in familial multiple system tauopathy, and oligodendroglial degeneration is the histological hallmark of multiple system atrophy (MSA).
Other components of the cytoskeleton are also essential for process outgrowth and myelin formation. Disruption of the actin cytoskeleton prevents spiralling of the myelinating process in Schwann cells. Rho kinase (ROCK) is a key regulator of myelinating process extension in Schwann cells and oligodendrocytes. ROCK phosphorylates myosin and is an effector of Rho, which regulates the actin cytoskeleton. ROCK signalling regulates the 1:1 relationship between Schwann cells and axons, and disruption of ROCK results in Schwann cells myelinating multiple internodes. In oligodendrocytes, activation of ROCK results in myelin process retraction involving S1P5 and Fyn. By contrast, activation of Cdc42 by Fyn causes process extension.
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