Molecular mechanisms of localised Myelin Basic Protein synthesis in oligodendrocytes
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Oligodendrocytes myelinate axons in the central nervous system (CNS) accelerating rapid action potential transmission by saltatory conduction. Myelin basic protein (MBP) is an indispensable constituent of myelin and its absence leads to severe hypomyelination in the CNS. Mbp mRNA is transported to the plasma membrane in specific granules in a translationally silenced state. Mechanisms that control/regulate local MBP synthesis remain however elusive. In this project we show that local translation of MBP RNA at distal oligodendrocytic processes dynamically depends on ionic milieu. Plasma membrane located Na+,Ca2+ exchanger and Na+,K+-ATPase and intracellular Ca2+-gated Ca2+ channels (ryanodine receptors) contribute to generation of spatially and temporally confined calcium transients that modulate local MBP synthesis. As Na+,Ca2+ exchanger and Na+,K+-ATPase are electrogenic, they may serve as sensors of neuronal activity in vivo. Ago proteins and small RNAs form the minimal core of the RNA induced silencing complex and together recognize target mRNAs to be translationally inhibited or degraded. We show that Argonaute proteins (Ago1-4) are expressed by oligodendrocytes and that Ago2 colocalizes with hnRNPA2 in granular cytoplasmic structures. We show that Ago2 associates with hnRNPA2, MbpmRNA, sncRNA715 and Fyn kinase and is tyrosine phosphorylated in response to Fyn activity, suggesting an involvement of Ago2 in the translational regulation of Mbp. In addition to Mbp, other A2RE-containing mRNAs are transported in hnRNP-A2-dependent RNA granules, including oligodendroglial myelin-associated oligodendrocytic basic protein (MOBP). The function of MOBP has been associated with the compaction and stabilization of myelin membranes, but despite its high abundance the role of MOBP at the cellular level remains unknown. We show that MPBP translation is regulated by Fyn kinase, similar to MBP, and MOBP knockdown/overexpressison affects the morphological differentiation of oligodendrocytes.
Publications
- (2020) Ryanodine receptor- and sodium-calcium exchanger-mediated spontaneous calcium activity in immature oligodendrocytes in cultures. Neuroscience letters 732 134913
Bassetti, Davide; Hammann, Jens; Luhmann, Heiko J.; White, Robin; Kirischuk, Sergei
(See online at https://doi.org/10.1016/j.neulet.2020.134913) - (2015). Oligodendroglial Argonaute protein Ago2 associates with molecules of the Mbp mRNA localization machinery and is a downstream target of Fyn kinase. Front Cell Neurosci 9
Müller C, Schäfer I, Luhmann HJ & White R
(See online at https://doi.org/10.3389/fncel.2015.00328) - (2016). Intracellular ion signaling influences myelin basic protein synthesis in oligodendrocyte precursor cells. Cell Calcium 60, 322-330
Friess M, Hammann J, Unichenko P, Luhmann HJ, White R & Kirischuk S
(See online at https://doi.org/10.1016/j.ceca.2016.06.009) - (2016). MOBP levels are regulated by Fyn kinase and affect the morphological differentiation of oligodendrocytes. J Cell Sci 129, 930-942
Schäfer I, Müller C, Luhmann HJ & White R
(See online at https://doi.org/10.1242/jcs.172148) - (2018). alpha2 isoform of Na(+),K(+)-ATPase via Na(+),Ca(2+) exchanger modulates myelin basic protein synthesis in oligodendrocyte lineage cells in vitro. Cell Calcium 73, 1-10
Hammann J, Bassetti D, White R, Luhmann HJ & Kirischuk S
(See online at https://doi.org/10.1016/j.ceca.2018.03.003)
