Molecular mechanisms of inherited demyelinating neuropathies

Scherer, Steven S.; Wrabetz, Lawrence

doi:10.1002/glia.20751

Cited by 152 publications

(121 citation statements)

References 186 publications

(215 reference statements)

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“…Myelin biogenesis and maintenance is a complex process involving coordinated exocytosis, endocytosis, and cytoskeletal dynamics. Perturbations in the myelin protein trafficking and/or turnover are associated with major myelin pathologies (16,17). Current hypotheses suggest that recycling endosomes play a central role in protein sorting and trafficking, both during plasma membrane recycling and as an intermediate step during cargo transport from the trans-Golgi network to the plasma membrane (18).…”

Section: Discussionmentioning

confidence: 99%

SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system

Arnaud¹,

Zenker

Charles³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

100

105

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Charcot–Marie–Tooth disease type 4C (CMT4C) is an early-onset, autosomal recessive form of demyelinating neuropathy. The clinical manifestations include progressive scoliosis, delayed age of walking, muscular atrophy, distal weakness, and reduced nerve conduction velocity. The gene mutated in CMT4C disease, SH3TC2 / KIAA1985 , was recently identified; however, the function of the protein it encodes remains unknown. We have generated knockout mice where the first exon of the Sh3tc2 gene is replaced with an enhanced GFP cassette. The Sh3tc2 Δ Ex1 /Δ Ex1 knockout animals develop progressive peripheral neuropathy manifested by decreased motor and sensory nerve conduction velocity and hypomyelination. We show that Sh3tc2 is specifically expressed in Schwann cells and localizes to the plasma membrane and to the perinuclear endocytic recycling compartment, concordant with its possible function in myelination and/or in regions of axoglial interactions. Concomitantly, transcriptional profiling performed on the endoneurial compartment of peripheral nerves isolated from control and Sh3tc2 Δ Ex1 /Δ Ex1 animals uncovered changes in transcripts encoding genes involved in myelination and cell adhesion. Finally, detailed analyses of the structures composed of compact and noncompact myelin in the peripheral nerve of Sh3tc2 Δ Ex1 /Δ Ex1 animals revealed abnormal organization of the node of Ranvier, a phenotype that we confirmed in CMT4C patient nerve biopsies. The generated Sh3tc2 knockout mice thus present a reliable model of CMT4C neuropathy that was instrumental in establishing a role for Sh3tc2 in myelination and in the integrity of the node of Ranvier, a morphological phenotype that can be used as an additional CMT4C diagnostic marker.

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Section: Discussionmentioning

confidence: 99%

SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system

Arnaud¹,

Zenker

Charles³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

100

105

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“…This factor is most likely the major contributor to long-term disability in human patients and animal models (Scherer and Wrabetz, 2008). It is thought that the damage inflicted on axons on an SC-specific mutation more likely derives from demyelination, disruption of SC trophic support toward axons, or the production of toxic influences than from a primary lack of myelin (Nave and Trapp, 2008).…”

Section: Selective Dicer Inactivation In Schwann Cells Results In Axomentioning

confidence: 99%

“…The importance of myelin is highlighted in demyelinating neuropathies, which result in loss of motor and sensory abilities (Scherer and Wrabetz, 2008). SCs arise from neural crest cells (NCCs) (Jessen and Mirsky, 2005), a migratory population that delaminates from the neural tube early in embryonic development (Woodhoo and Sommer, 2008).…”

Section: Introductionmentioning

confidence: 99%

Dicer in Schwann Cells Is Required for Myelination and Axonal Integrity

Pereira

Baumann²,

Norrmén³

et al. 2010

J. Neurosci.

113

104

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Dicer is responsible for the generation of mature micro-RNAs (miRNAs) and loading them into RNA-induced silencing complex (RISC). RISC functions as a probe that targets mRNAs leading to translational suppression and mRNA degradation. Schwann cells (SCs) in the peripheral nervous system undergo remarkable differentiation both in morphology and gene expression patterns throughout lineage progression to myelinating and nonmyelinating phenotypes. Gene expression in SCs is particularly tightly regulated and critical for the organism, as highlighted by the fact that a 50% decrease or an increase to 150% of normal gene expression of some myelin proteins, like PMP22, results in peripheral neuropathies. Here, we selectively deleted Dicer and consequently gene expression regulation by mature miRNAs from Mus musculus SCs. Our results show that in the absence of Dicer, most SCs arrest at the promyelinating stage and fail to start forming myelin. At the molecular level, the promyelinating transcription factor Krox20 and several myelin proteins [including myelin associated glycoprotein (MAG) and PMP22] were strongly reduced in mutant sciatic nerves. In contrast, the myelination inhibitors SOX2, Notch1, and Hes1 were increased, providing an additional potential basis for impaired myelination. A minor fraction of SCs, with some peculiar differences between sensory and motor fibers, overcame the myelination block and formed unusually thin myelin, in line with observed impaired neuregulin and AKT signaling. Surprisingly, we also found signs of axonal degeneration in Dicer mutant mice. Thus, our data indicate that miRNAs critically regulate Schwann cell gene expression that is required for myelination and to maintain axons via axon-glia interactions.

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“…The differentiation state of the myelin Schwann cell is not fixed, unlike that of its relative the oligodendrocyte, and the cell can readily be destabilized (Jessen and Mirsky 2008). On the one hand, this renders the cells vulnerable to immune assaults or genetic abnormalities seen in demyelinating neuropathies and in tumors in which Schwann cells exist in varying, poorly characterized demyelinated states and/or proliferate abnormally (Scherer and Wrabetz 2008;Lehmann et al 2012;Ribeiro et al 2013). On the other hand, the plasticity of myelin cells allows them to respond adaptively to injury by converting to cells that support regeneration.…”

Section: Schwann Cell Plasticitymentioning

confidence: 99%

Schwann Cells: Development and Role in Nerve Repair

Jessen

Mirsky

Lloyd

2015

Cold Spring Harb Perspect Biol

607

539

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Schwann cells develop from the neural crest in a well-defined sequence of events. This involves the formation of the Schwann cell precursor and immature Schwann cells, followed by the generation of the myelin and nonmyelin (Remak) cells of mature nerves. This review describes the signals that control the embryonic phase of this process and the organogenesis of peripheral nerves. We also discuss the phenotypic plasticity retained by mature Schwann cells, and explain why this unusual feature is central to the striking regenerative potential of the peripheral nervous system (PNS).T he myelin and nonmyelin (Remak) Schwann cells of adult nerves originate from the neural crest in well-defined developmental steps ( Fig. 1). This review focuses on embryonic development (for additional information on myelination, see Salzer 2015). We also discuss how the ability to change between differentiation states, a characteristic attribute of developing cells, is retained by mature Schwann cells, and explain how the ability of Schwann cells to change phenotype in response to injury allows the peripheral nervous system (PNS) to regenerate after damage. TWO TYPES OF EMBRYONIC NERVESAdult nerves are stable structures in which the nerve fibers are protected structurally by a collagen-rich, vascularized extracellular matrix (the endoneurium) linked to the basal lamina surrounding each axon -Schwann cell unit. The endoneurial environment is further protected by a surrounding multilayered cellular tube (the perineurium) that shields the nerve fibers from unwanted cells and molecules (Fig. 2).A more dynamic and radically different structure, reminiscent of axon -glial organization in the central nervous system (CNS), is seen in early embryonic nerves (embryo day E14/15 in rat hind limb and E12/13 in mouse). These nerves consist of tightly packed axons and flattened, glial cell processes without significant extracellular space, matrix, or basal lamina. The glial cell bodies lie among the axons inside the nerve or at the nerve surface. These cells represent the first stage of the Schwann cell lineage, Schwann cell precursors (Figs. 3 and 4).

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Molecular mechanisms of inherited demyelinating neuropathies

Cited by 152 publications

References 186 publications

SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system

SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system

Dicer in Schwann Cells Is Required for Myelination and Axonal Integrity

Schwann Cells: Development and Role in Nerve Repair

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