Biology and pathology of nonmyelinating Schwann cells

Griffin, John W.; Thompson, Wesley J.

doi:10.1002/glia.20778

Cited by 251 publications

(206 citation statements)

References 131 publications

(196 reference statements)

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“…The greatest number of M cells containing brain homogenate was found in those animals that survived 10 to 60 min prior to the initiation of perfusion, with a noticeable drop in the number of M cells containing brain homogenate in those animals that survived 180 min ( Table 1). Analysis of tissue deep within the M cell layer was restricted to tissue sections processed for PrP d IHC, since GFAP labels thin-diameter nonmyelinating Schwann cells (29,39), which are located deep within M cells, in the NALT, and coursing through the lamina propria ( Fig. 2D and 4E).…”

Section: Resultsmentioning

confidence: 99%

Rapid Transepithelial Transport of Prions following Inhalation

Kincaid

Hudson

Richey

et al. 2012

J Virol

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Prion infection and pathogenesis are dependent on the agent crossing an epithelial barrier to gain access to the recipient nervous system. Several routes of infection have been identified, but the mechanism(s) and timing of in vivo prion transport across an epithelium have not been determined. The hamster model of nasal cavity infection was used to determine the temporal and spatial parameters of prion-infected brain homogenate uptake following inhalation and to test the hypothesis that prions cross the nasal mucosa via M cells. A small drop of infected or uninfected brain homogenate was placed below each nostril, where it was immediately inhaled into the nasal cavity. Regularly spaced tissue sections through the entire extent of the nasal cavity were processed immunohistochemically to identify brain homogenate and the disease-associated isoform of the prion protein (PrP d ). Infected or uninfected brain homogenate was identified adhering to M cells, passing between cells of the nasal mucosa, and within lymphatic vessels of the nasal cavity at all time points examined. PrP d was identified within a limited number of M cells 15 to 180 min following inoculation, but not in the adjacent nasal mucosa-associated lymphoid tissue (NALT). While these results support M cell transport of prions, larger amounts of infected brain homogenate were transported paracellularly across the respiratory, olfactory, and follicle-associated epithelia of the nasal cavity. These results indicate that prions can immediately cross the nasal mucosa via multiple routes and quickly enter lymphatics, where they can spread systemically via lymph draining the nasal cavity.

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Section: Resultsmentioning

confidence: 99%

Rapid Transepithelial Transport of Prions following Inhalation

Kincaid

Hudson

Richey

et al. 2012

J Virol

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“…ϩ T cells or their effector molecules act directly on neurons to prevent axon regeneration, or that they act on Schwann cells that are required for axonal regeneration following Wallerian degeneration (24).…”

Section: Discussionmentioning

confidence: 99%

Reversible Nerve Damage and Corneal Pathology in Murine Herpes Simplex Stromal Keratitis

Yun

Rowe

Lathrop

et al. 2014

J Virol

108

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Herpes simplex virus type 1 (HSV-1) shedding from sensory neurons can trigger recurrent bouts of herpes stromal keratitis (HSK), an inflammatory response that leads to progressive corneal scarring and blindness. A mouse model of HSK is often used to delineate immunopathogenic mechanisms and bears many of the characteristics of human disease, but it tends to be more chronic and severe than human HSK. Loss of blink reflex (BR) in human HSK is common and due to a dramatic retraction of corneal sensory nerve termini in the epithelium and the nerve plexus at the epithelial/stromal interface. However, the relationship between loss of BR due to nerve damage and corneal pathology associated with HSK remains largely unexplored. Here, we show a similar retraction of corneal nerves in mice with HSK. Indeed, we show that much of the HSK-associated corneal inflammation in mice is actually attributable to damage to the corneal nerves and accompanying loss of BR and can be prevented or ameliorated by tarsorrhaphy (suturing eyelids closed), a clinical procedure commonly used to prevent corneal exposure and desiccation. In addition, we show that HSK-associated nerve retraction, loss of BR, and severe pathology all are reversible and regulated by CD4 ؉ T cells. Thus, defining immunopathogenic mechanisms of HSK in the mouse model will necessitate distinguishing mechanisms associated with the immunopathologic response to the virus from those associated with loss of corneal sensation. Based on our findings, investigation of a possible contribution of nerve damage and BR loss to human HSK also appears warranted. IMPORTANCEHSK in humans is a potentially blinding disease characterized by recurrent inflammation and progressive scarring triggered by viral release from corneal nerves. Corneal nerve damage is a known component of HSK, but the causes and consequences of HSK-associated nerve damage remain obscure. We show that desiccation of the corneal surface due to nerve damage and associated loss of BR severely exacerbates and prolongs inflammation-induced pathology in mice. Preventing corneal desiccation results in a milder and more transient HSK with variable scarring that mirrors HSK seen in most humans. We further show that nerve damage is reversible and regulated by CD4 ؉ T cells. Thus, we provide a mouse model that more closely resembles typical human HSK and suggest nerve damage is an important but largely overlooked factor in human disease.

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“…3Bc), and the very small-caliber axons were engaged by nonmyelinating SCs as Remak bundles (Fig. 3Be, white arrows), a structure that differs from bundles of unsorted axons because the SC extends processes that contact every single axon (Griffin and Thompson, 2008) instead of simply surrounding the group. Dicer mutant SNs still presented a large number of 1:1 not-myelinated profiles (Fig.…”

Section: Myelination Defects In Dicer Mutant Scsmentioning

confidence: 99%

Dicer in Schwann Cells Is Required for Myelination and Axonal Integrity

Pereira

Baumann²,

Norrmén³

et al. 2010

J. Neurosci.

112

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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Biology and pathology of nonmyelinating Schwann cells

Cited by 251 publications

References 131 publications

Rapid Transepithelial Transport of Prions following Inhalation

Rapid Transepithelial Transport of Prions following Inhalation

Reversible Nerve Damage and Corneal Pathology in Murine Herpes Simplex Stromal Keratitis

Dicer in Schwann Cells Is Required for Myelination and Axonal Integrity

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