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Analysis of the molecular mechanisms underlying CNS myelination, in vitro and in vivo

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandling

  • Jes Steengaard
Higher brain function depend on fast saltatory propagation of action potentials, facilitated by the presence of the myelin sheath. Myelin sheaths consist of multiple layers of oligodendrocyte membrane wrapped around the axons of neurons. Myelin layers consist of compacted and noncompacted membrane. Membrane compaction is achieved by the binding of MBP to the inner leaflets of the membrane. Tight spatial and temporal control of translation of MBP mRNA is highly dependent on transport processes and intracellular signaling to proteins
The myelin related disease multiple sclerosis is caused by multiple environmental and genetic factors giving an increased susceptibility of developing multiple sclerosis. Single nucleotide polymorphisms (SNPs) near the KIF21B gene, has been suggested with an increased risk of developing multiple sclerosis.
I investigated and characterized the expression of the two MBP zebrafish orthologues Mbpa and Mbpb. I generated three transgenic zebrafish lines, expressing the photoconvertible Dendra2 in mature oligodendrocytes, controlled by the Mbpa promoter. With these transgenic lines, I were able to show that the 3’UTRs of MBP mRNA repress translation in vivo and influences transport of mRNA to the myelin sheath. These transgenic lines are additionally used to show, that activation of myelination, from neuronal activity, is through cAMP- or BDNF-stimulation of translation of MBP mRNA.
Additionally, through overexpression and knockdown I show that KIF21B impact process outgrowth and the differentiation and proliferation of cultured oligodendrocytes. Following this, morpholino induced knockdown in zebrafish results in a decrease in mature oligodendrocytes and possibly an increase in oligodendrocyte precursor cells.
Together, these results provide new tools for investigating mRNA translation in vivo, along with a novel regulator of myelination.
ForlagDepartment of Molecular Biology, Aarhus University
Antal sider137
StatusUdgivet - jul. 2019

Note vedr. afhandling

Forsvarsdato: 26.06.19<br/>Supervisor: Lisbeth Schmidt laursen and Claus Oxvig<br/>Termination date: 01.07.2019

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