Schwann cell myelination requires Dynein function.

Melissa M Langworthy,Bruce Appel

doi:10.1186/1749-8104-7-37

Abstract

BackgroundInteraction of Schwann cells with axons triggers signal transduction that drives expression of Pou3f1 and Egr2 transcription factors, which in turn promote myelination. Signal transduction appears to be mediated, at least in part, by cyclic adenosine monophosphate (cAMP) because elevation of cAMP levels can stimulate myelination in the absence of axon contact. The mechanisms by which the myelinating signal is conveyed remain unclear.ResultsBy analyzing mutations that disrupt myelination in zebrafish, we learned that Dynein cytoplasmic 1 heavy chain 1 (Dync1h1), which functions as a motor for intracellular molecular trafficking, is required for peripheral myelination. In dync1h1 mutants, Schwann cell progenitors migrated to peripheral nerves but then failed to express Pou3f1 and Egr2 or make myelin membrane. Genetic mosaic experiments revealed that robust Myelin Basic Protein expression required Dync1h1 function within both Schwann cells and axons. Finally, treatment of dync1h1 mutants with a drug to elevate cAMP levels stimulated myelin gene expression.ConclusionDync1h1 is required for retrograde transport in axons and mutations of Dync1h1 have been implicated in axon disease. Our data now provide evidence that Dync1h1 is also required for efficient myelination of peripheral axons by Schwann cells, perhaps by facilitating signal transduction necessary for myelination.

Highlights

Interaction of Schwann cells with axons triggers signal transduction that drives expression of Pou3f1 and Egr2 transcription factors, which in turn promote myelination
A missense mutation that changes an amino acid within the homodimerization domain of Dynein cytoplasmic 1 heavy chain 1 (Dync1h1) has been found in affected members of a family diagnosed with a dominant, axonal form of Charcot-Marie-Tooth (CMT) Disease [2] that is characterized by distal muscle weakness and atrophy, and mutations of the p150Glued subunit of Dynactin, which interacts with Dync1h1, have been identified in families with slowly progressive lower motor neuron disease and amyotrophic lateral sclerosis [3,4]
Results dync1h1 function is essential for Schwann cell myelin basic protein expression In a forward genetic screen for mutations that disrupt glial development, we identified an allele of dync1h1 that caused both central nervous system (CNS) and peripheral nervous system (PNS) myelination defects

Summary

Introduction

Interaction of Schwann cells with axons triggers signal transduction that drives expression of Pou3f1 and Egr transcription factors, which in turn promote myelination. Motor control and sensation require that nerve impulses are rapidly and efficiently transmitted over long distances. This is achieved by axons, which relay electrical signals between the central nervous system and peripheral muscles and sensory elements, and Schwann cells, which enhance the speed and efficiency of signal propagation by ensheathing peripheral axons with insulating myelin. Investigation of the molecular mechanisms of peripheral nerve disease has revealed that disruption of axon transport can cause nerve dysfunction and degeneration [1]. Whether disruption of Dynein-mediated molecular transport in other cellular components of peripheral nerves contributes to disease is not known

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