Molecular Interactions between Neurons and Oligodendrocytes during Myelin Formation

Dissertation for the award of the degree "Doctor rerum naturalium" Division of Mathematics and Natural Sciences of the Georg-August-Universität Göttingen

by Sebastian Timmler
Doctoral thesis
Date of Examination:2018-09-17
Date of issue:2019-04-23
Advisor:Prof. Dr. Mikael Simons
Referee:Prof. Dr. Mikael Simons
Referee:Prof. Dr. Blanche Schwappach
Persistent Address: http://dx.doi.org/10.53846/goediss-7396

 

 

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Abstract

English

Myelin is a multi-layered membrane wrapped around axons. It allows fast nerve conduction and provides the axon with trophic support. In the central nervous sys- tem (CNS), oligodendrocytes form multiple myelin sheaths. Thus, a single oligo- dendrocyte has to coordinate the generation of numerous myelin segments on dif- ferent axons. A cellular model of myelin sheath generation has been provided, but the molecular mechanisms of multiple aspects of myelination such as initiation, lat- eral growth and termination are still elusive. During myelination, the inner leaflet is actively growing by adding new membrane layers to the sheath. At the same time, the sheath is growing laterally and the outer layers are starting to compact. The ad- hesion molecules forming the paranodal Caspr/Cntn1/Nfasc155 complex are essen- tial for the formation of the Nodes of Ranvier (gaps inbetween individual sheaths), but whether they might play a role in guiding myelin growth and wrapping is not known. In this study, we combined high-resolution live imaging with newest ultra-structure resolving 3D electron microscopy techniques to assess the role of the mayor axon- glial adhesion factors. We sequentially reduced internodal (Mag) and paranodal (Caspr/Cntn1/Nfasc155) adhesion in zebrafish by Crispr/Cas9 gene editing and in mice by crossbreeding of established mutant lines. Zebrafish mutants exhibited myelinated cell bodies, decreased sheath length, impaired sheath growth dynamics and double myelinated sheaths. Consistent with the zebrafish data, double mutants in mice showed hypomyelination, reduced sheath length and split myelin sheaths. The split myelin sheaths could be identified as either overgrown double myelin segments or aberrant wrapping by a divided, misguided inner tongue, that we call "inside-out-wrapping". In our model we propose, that axon-oligodendroglial ad- hesion is essential for lateral growth, precise wrapping and correct targeting of the myelin sheath. This results do not only provide new insights into myelin biology, but may also have implications for our understanding of myelin formation in neu- rological diseases.
Keywords: Myelin; Adhesion molecules; Central nervous system; Caspr; Mag
 
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