Oligodendrocyte Neurofascin Independently Regulates Both Myelin Targeting and Sheath Growth in the CNS.

Anna Klingseisen,Rafael G. Almeida,Linde Kegel,Richard J. Poole,Maria Rubio-Brotons,Sigrid Koudelka,Diane L. Sherman,Silvia K. Benito-Kwiecinski,Peter J. Brophy,Ana-Maria Ristoiu,David A. Lyons

doi:10.1016/j.devcel.2019.10.016

Anna Klingseisen, Rafael G. Almeida

Open Access

https://doi.org/10.1016/j.devcel.2019.10.016

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Abstract

SummarySelection of the correct targets for myelination and regulation of myelin sheath growth are essential for central nervous system (CNS) formation and function. Through a genetic screen in zebrafish and complementary analyses in mice, we find that loss of oligodendrocyte Neurofascin leads to mistargeting of myelin to cell bodies, without affecting targeting to axons. In addition, loss of Neurofascin reduces CNS myelination by impairing myelin sheath growth. Time-lapse imaging reveals that the distinct myelinating processes of individual oligodendrocytes can engage in target selection and sheath growth at the same time and that Neurofascin concomitantly regulates targeting and growth. Disruption to Caspr, the neuronal binding partner of oligodendrocyte Neurofascin, also impairs myelin sheath growth, likely reflecting its association in an adhesion complex at the axon-glial interface with Neurofascin. Caspr does not, however, affect myelin targeting, further indicating that Neurofascin independently regulates distinct aspects of CNS myelination by individual oligodendrocytes in vivo.

Highlights

Myelination in the central nervous system (CNS), by oligodendrocytes, starts around birth, and continues into adult life, with specific axons and circuits myelinated in stereotyped patterns at distinct times
We identified a mutation in neurofascin b, which caused mistargeting of myelin to cell bodies and impaired myelin sheath growth along axons
We found that loss of Caspr, the axonal binding partner of oligodendrocyte Neurofascin, impaired sheath growth, likely reflecting their known association in an adhesion complex at the axon-glial interface (Bhat et al, 2001; Einheber et al, 1997; Sherman et al, 2005)

Summary

Introduction

Myelination in the central nervous system (CNS), by oligodendrocytes, starts around birth, and continues into adult life, with specific axons and circuits myelinated in stereotyped patterns at distinct times. Studies in zebrafish and rodents indicate that oligodendrocytes have a period on the order of hours during which they select axons for myelination and initiate myelin sheath growth (Czopka et al, 2013; Watkins et al, 2008). During this time, oligodendrocytes extend dynamic processes that interact with multiple targets, making myelin sheaths on specific axons, while retracting from incorrect targets, including inappropriate axons and cell bodies (Almeida et al, 2018; Baraban et al, 2018; Czopka et al, 2013; Hines et al, 2015; Mensch et al, 2015). Recent studies have provided insight into the dynamics of CNS myelination, the mechanisms by which oligodendrocytes coordinate myelin targeting and growth remain unclear

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