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 6

Treatment with GSK3β inhibitors restores Schwann cell differentiation and radial sorting defects.

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Treatment with GSK3β inhibitors restores Schwann cell differentiation an...
(A) In vitro myelination after treatment with NaCl (control) or LiCl. *P = 0.001. (B) Strategy for in vivo treatments. For the assessment of LiCl on the phosphorylation of AKT and GSK3β, mice were injected with LiCl on alternating days from P7 to P15 (upper diagram). For the assessment of LiCl on nerve pathology, mice were injected daily with LiCl from P1 to P6 (lower diagram). (C and D) Quantification of p-GSK3β at Tyr216 (*P = 0.04) (C) and Ser9 (*P = 0.017) (D) in nerves from P15 mice. (E and F) Quantification of p-AKT at Ser473 (E) and Thr308 (F) in nerves from P15 mice. *P = 0.01. (G and H) Quantification of SOX2 (G) and OCT6 (H) levels in nerves from P6 WT and Gnpat-KO mice. *P = 0.03 (G); P = 0.038 (H). (I) Ultrastructural analysis of sciatic nerves from P6 Gnpat-KO mice treated with NaCl and LiCl. Lines and asterisks indicate axon bundles on control and lithium-treated nerves, respectively. Scale bars: 5 μm. (J) Number of axons in bundles of sciatic nerves from P6 mice treated with NaCl and LiCl. *P = 0.0013. (K) Density of sorted axons (promyelinating stage) in sciatic nerves from P6 mice treated with NaCl and LiCl. *P = 0.0022. (L) Number of axons in bundles of sciatic nerves from P4 mice treated with DMSO and TDZD-8. *P < 0.007. (M) Density of sorted axons in sciatic nerves from P4 WT and Gnpat-KO mice treated with DMSO and TDZD-8. *P < 0.03.