Transcriptional Expression of Myelin Basic Protein in Oligodendrocytes Depends on Functional Syntaxin 4: a Potential Correlation with Autocrine Signaling

Abstract

bMyelination of axons by oligodendrocytes is essential for saltatory nerve conduction. To form myelin membranes, a coordinated synthesis and subsequent polarized transport of myelin components are necessary. Here, we show that as part of the mechanism to establish membrane polarity, oligodendrocytes exploit a polarized distribution of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) machinery components syntaxins 3 and 4, localizing to the cell body and the myelin membrane, respectively. Our data further reveal that the expression of myelin basic protein (MBP), a myelin-specific protein that is synthesized "on site" after transport of its mRNA, depends on the correct functioning of the SNARE machinery, which is not required for mRNA granule assembly and transport per se. Thus, downregulation and overexpression of syntaxin 4 but not syntaxin 3 in oligodendrocyte progenitor cells but not immature oligodendrocytes impeded MBP mRNA transcription, thereby preventing MBP protein synthesis. The expression and localization of another myelin-specific protein, proteolipid protein (PLP), was unaltered. Strikingly, conditioned medium obtained from developing oligodendrocytes was able to rescue the block of MBP mRNA transcription in syntaxin 4-downregulated cells. These findings indicate that the initiation of the biosynthesis of MBP mRNA relies on a syntaxin 4-dependent mechanism, which likely involves activation of an autocrine signaling pathway.

Transient Improvement of Cerebellar Oligodendroglial Development in a Neonatal Hyperoxia Model by PDGFA Treatment

“…A major function of mature oligodendrocytes is the myelination of axons by the formation of myelin. MBP is essential for myelination (Baumann and Pham‐Dinh, ; Bijlard et al , ). Neonatal hyperoxia causes myelin deficits in the cerebellum long‐term, as determined by impaired expression of MBP in the cerebellum until young adult ages (Scheuer et al , ).…”

Encapsulated oligodendrocyte precursor cell fate is dependent on PDGF‐AA release kinetics in a 3D microparticle‐hydrogel drug delivery system

“…Transcription of the MBP RNA is a complex process which requires upregulation of other proteins and downregulation of inhibitory proteins. Therefore, it is possible that the delivery of PDGF‐AA alone is not sufficient to induce MBP protein expression . PDGFR protein expression is observed across all groups, with the highest levels of expression in groups that received bolus PDGF‐AA and continuous PDGF‐AA (Fig.…”

Oligodendroglial membrane dynamics in relation to myelin biogenesis

“…This shows that OLGs display a ‘unique’ polarity, where the cell body with the basolateral-like composition is targeted by an apical-like trafficking mechanism whereas the more apical-like myelin membrane is targeted by a basolateral-like mechanism. Consistently, the t-SNAREs syntaxin 3 and 4, which are distributed in a distinct polarized fashion in polarized cells, localize in OLGs to the plasma membrane and myelin membrane, respectively [ 2 , 49 ]. Similarly, as reported for its transport in epithelial cells, the apical membrane protein marker hemagglutinin (HA) of influenza virus is delivered to the apical-like cell body plasma membrane in OLGs, while the VSV G protein, a basolateral marker in epithelial cells, is delivered to the myelin sheet [ 48 ].…”

“…From the latter membrane, newly arrived PLP appears to be internalized via a sulfatide-mediated and clathrin-independent but cholesterol-dependent pathway [ 51 ], and it has been proposed that endosomal compartments may subsequently serve as site of storage, prior to a neuronal signal-triggered delivery of the protein to the myelin membrane, as inferred from data obtained in Oli-neu cells [ 51 ]. By contrast, the peripheral membrane protein MBP, another major myelin protein, is translated ‘on site’, following transport of MBP mRNA containing granules towards the myelin sheet [ 3 , 49 ]. During the process of myelin wrapping around the axon, both PLP protein and MBP mRNA are continuously trafficking towards the myelin membrane via cytoplasmic channels near the non-compacted edges of the newly assembling myelin membrane (Fig.…”