Abstract
Central nervous system myelin is a multilayered membrane produced by oligodendrocytes to increase neural processing speed and efficiency, but the molecular mechanisms underlying axonal selection and myelin wrapping are unknown. Here, using combined morphological and molecular analyses in mice and zebrafish, we show that adhesion molecules of the paranodal and the internodal segment work synergistically using overlapping functions to regulate axonal interaction and myelin wrapping. In the absence of these adhesive systems, axonal recognition by myelin is impaired with myelin growing on top of previously myelinated fibers, around neuronal cell bodies and above nodes of Ranvier. In addition, myelin wrapping is disturbed with the leading edge moving away from the axon and in between previously formed layers. These data show how two adhesive systems function together to guide axonal ensheathment and myelin wrapping, and provide a mechanistic understanding of how the spatial organization of myelin is achieved.
Highlights
Central nervous system myelin is a multilayered membrane produced by oligodendrocytes to increase neural processing speed and efficiency, but the molecular mechanisms underlying axonal selection and myelin wrapping are unknown
Some of these molecules are localized at the paranodal and internodal segment, among which are the immunoglobulin cell adhesion molecules (Cadm) (i.e., Cadm3/Necl1/SynCAM1 and Cadm4/ Necl4/SynCAM4)[24,25] and the Sialic acid-binding immunoglobulin-type lectins family of proteins
Expression of caspr-YFP in neurons and nfascbEGFP in glia resulted in paranodal distribution (Supplementary Fig. 1c, d), indicating that cntn1b, nfascb and caspr are localized to the axo-glial junction in zebrafish
Summary
Central nervous system myelin is a multilayered membrane produced by oligodendrocytes to increase neural processing speed and efficiency, but the molecular mechanisms underlying axonal selection and myelin wrapping are unknown. Using combined morphological and molecular analyses in mice and zebrafish, we show that adhesion molecules of the paranodal and the internodal segment work synergistically using overlapping functions to regulate axonal interaction and myelin wrapping. Some of these molecules are localized at the paranodal and internodal segment (the portion of the axonal/glial membrane located under the compact myelin sheath), among which are the immunoglobulin cell adhesion molecules (Cadm) (i.e., Cadm3/Necl1/SynCAM1 and Cadm4/ Necl4/SynCAM4)[24,25] and the Sialic acid-binding immunoglobulin-type lectins family of proteins (myelin-associated glycoprotein, MAG) These adhesion molecules are ideally positioned to drive myelin growth at the innermost myelin membrane, but the phenotype of the respective knockout mice is subtle with morphologically intact myelin and only minor changes in myelin integrity[26,27,28]. Our data support a model in which these two adhesive systems work together to clamp the leading edge to the axon allowing the extending leading edge to move around the axon without forming promiscuous contacts
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