Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination
Tiago Ferreira da Silva, … , Mónica M. Sousa, Pedro Brites
Tiago Ferreira da Silva, … , Mónica M. Sousa, Pedro Brites
Published April 24, 2014
Citation Information: J Clin Invest. 2014;124(6):2560-2570. https://doi.org/10.1172/JCI72063.
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Research Article Neuroscience

Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

Abstract

Rhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue and myelin; however, the role of plasmalogens in the peripheral nervous system is poorly defined. Here, we used mouse models of RCDP and analyzed the consequence of plasmalogen deficiency in peripheral nerves. We determined that plasmalogens are crucial for Schwann cell development and differentiation and that plasmalogen defects impaired radial sorting, myelination, and myelin structure. Plasmalogen insufficiency resulted in defective protein kinase B (AKT) phosphorylation and subsequent signaling, causing overt activation of glycogen synthase kinase 3β (GSK3β) in nerves of mutant mice. Treatment with GSK3β inhibitors, lithium, or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) restored Schwann cell defects, effectively bypassing plasmalogen deficiency. Our results demonstrate the requirement of plasmalogens for the correct and timely differentiation of Schwann cells and for the process of myelination. In addition, these studies identify a mechanism by which the lack of a membrane phospholipid causes neuropathology, implicating plasmalogens as regulators of membrane and cell signaling.

Authors

Tiago Ferreira da Silva, Jessica Eira, André T. Lopes, Ana R. Malheiro, Vera Sousa, Adrienne Luoma, Robin L. Avila, Ronald J.A. Wanders, Wilhelm W. Just, Daniel A. Kirschner, Mónica M. Sousa, Pedro Brites

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Figure 1

Plasmalogen deficiency causes defects in axonal sorting and myelination.

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Plasmalogen deficiency causes defects in axonal sorting and myelination....
(A) Electron microscopic analysis of sciatic nerves from P5 and P15 WT and Gnpat-KO mice. Bundles in P5 Gnpat-KO nerves contained large axons (asterisks), whereas in WT nerves these axons had been sorted (arrowhead), and the bundles contained very small-caliber axons (arrow). At P15, sciatic nerves from Gnpat-KO mice had Remak bundles with only 1 axon (arrowheads). Scale bars: 2 μm. (B) Composition of axon bundles in sciatic nerves from P5 WT, Pex7-KO, and Gnpat-KO mice. *P = 0.031; **P = 0.011. (C) Density of sorted axons in sciatic nerves from P5 WT, Pex7-KO, and Gnpat-KO mice. *P = 0.003. (D) Composition of Remak bundles in nerves from adult WT and Pex7-KO mice. *P = 0.013. (E) Density of unmyelinated fibers (UMF) in Remak bundles of nerves from adult WT and Pex7-KO mice. (F) Quantification of myelin thickness by g ratio in sciatic nerves at P15. Results are graphed as boxes with a line at the mean and whiskers from the minimal to maximal values. *P = 0.005. (G) DRG cocultures of neurons and Schwann cells from WT and Gnpat-KO mice stained for neuronal βII-tubulin (green) and for the myelin protein MBP (red). Scale bars: 200 μm. (H) Density of myelin segments in DRG cocultures from WT and Gnpat-KO mice. *P = 0.001. (I) Length of individual myelin segments in myelinating cocultures. *P = 0.001.