A Laminin-2, Dystroglycan, Utrophin Axis Is Required for Compartmentalization and Elongation of Myelin Segments

Court, Felipe A.; Hewitt, Jane; Davies, Kay E.; Patton, Bruce L.; Uncini, Antonino; Wrabetz, Lawrence; Feltri, M. Laura

doi:10.1523/jneurosci.5672-08.2009

Cited by 64 publications

(85 citation statements)

References 47 publications

(77 reference statements)

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“…During development, βII spectrin was incorporated into bands of Cajal concomitant with myelin maturation (Fig. S1 B-E) (11). Immunoblot analysis of sciatic nerves and cultured Schwann cells further confirmed the presence of αII and βII spectrin and protein 4.1G (Fig.…”

Section: αIi and βIi Spectrin Form A Special Cytoskeleton In Myelinatmentioning

confidence: 69%

Schwann cell spectrins modulate peripheral nerve myelination

Susuki

Raphael²,

Ogawa³

et al. 2011

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

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During peripheral nerve development, Schwann cells ensheathe axons and form myelin to enable rapid and efficient action potential propagation. Although myelination requires profound changes in Schwann cell shape, how neuron-glia interactions converge on the Schwann cell cytoskeleton to induce these changes is unknown. Here, we demonstrate that the submembranous cytoskeletal proteins αII and βII spectrin are polarized in Schwann cells and colocalize with signaling molecules known to modulate myelination in vitro. Silencing expression of these spectrins inhibited myelination in vitro, and remyelination in vivo. Furthermore, myelination was disrupted in motor nerves of zebrafish lacking αII spectrin. Finally, we demonstrate that loss of spectrin significantly reduces both F-actin in the Schwann cell cytoskeleton and the Nectin-like protein, Necl4, at the contact site between Schwann cells and axons. Therefore, we propose αII and βII spectrin in Schwann cells integrate the neuron-glia interactions mediated by membrane proteins into the actin-dependent cytoskeletal rearrangements necessary for myelination.R apid and efficient action potential propagation in vertebrates depends on axon ensheathement by a multilammelar membrane sheath called myelin. Myelin is made by Schwann cells in the peripheral nervous system (PNS). During development, neuron-glia interactions induce reciprocal differentiation such that axons regulate Schwann cell differentiation, migration, and myelination, and Schwann cells regulate the organization of axonal membrane domains (1-3). The mechanisms regulating PNS myelination still remain poorly understood. In particular, myelination requires dramatic and dynamic changes in the Schwann cell cytoskeleton, leading to the profound changes in cell shape that accompany axonal ensheathement and wrapping. However, how axon-Schwann cell interactions converge on the Schwann cell cytoskeleton to induce these changes is unknown.A recent study suggests that submembranous cytoskeletal proteins, called spectrins, may contribute to myelination: a dominantnegative human mutation in αII spectrin causes severe cerebral hypomyelination (4). Spectrins are a family of extended, flexible cytoskeletal molecules consisting of α and β subunits (5). β-Spectrins interact with both the actin cytoskeleton and various membrane proteins via scaffolding proteins, such as ankyrins or 4.1 proteins. Spectrins are thought to (i) stabilize membrane protein complexes, (ii) provide mechanical support for cell membrane integrity, and (iii) serve as a multifunctional regulatory platform for cell signaling (6). Spectrins are abundantly expressed in the nervous system, but have traditionally been assumed to be mostly neuronal. For example, spectrins contribute to stabilization of axonal membrane domains including the node of Ranvier (7). Although spectrins were previously reported in myelinating Schwann cells, their specific isoforms and functions are not known (8).Here, we demonstrate that the submembranous cytoskeletal proteins in Schwann...

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Section: αIi and βIi Spectrin Form A Special Cytoskeleton In Myelinatmentioning

confidence: 69%

Schwann cell spectrins modulate peripheral nerve myelination

Susuki

Raphael²,

Ogawa³

et al. 2011

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

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“…4C) and are regulated by Sox10 in siRNA studies of the S16 Schwann cell line (51). Another laminin receptor is dystroglycan (Dag1), which interacts with the actin cytoskeleton and is required for Cajal band formation (50,58,66). Dystroglycan also interacts with Periaxin and Drp2 (50), and all three of these genes have prominent Sox10-binding sites (Fig.…”

Section: In Vivo Analysis Of Enhancer Dynamics After Nerve Injury-mentioning

confidence: 98%

Dynamic Regulation of Schwann Cell Enhancers after Peripheral Nerve Injury

Hung

Sun

Keleş

et al. 2015

Journal of Biological Chemistry

102

120

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Background: Nerve injury induces Schwann cells to remove myelin coating and secrete factors that stimulate nerve regeneration. Results: ChIP-seq was used to identify injury-regulated enhancers in peripheral nerve. Conclusion: Dynamically regulated enhancers identify target sequences of injury-regulated transcription factors in Schwann cells. Significance: These data elucidate transcription factor pathways that coordinate Schwann cell responses in peripheral nerve injury.

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“…Alternatively, the different developmental origin of Schwann cells that myelinate spinal roots versus distal nerves may underlie a different requirement for laminins and other molecules during radial sorting (Coulpier and others, 2009; Kucenas and others, 2008). Not all fibers are un-sorted in laminin mutants, but even those fibers that are successfully myelinated show abnormalities, namely nodes of Ranvier wider than normal, and short internodes (Court and others, 2009; Jaros and Jenkison, 1983). …”

Section: Radial Sorting and Human Neuropathiesmentioning

confidence: 99%

How Schwann Cells Sort Axons

Feltri¹,

Poitelon²,

2015

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Peripheral nerves contain large myelinated and small unmyelinated (Remak) fibers that perform different functions. The choice to myelinate or not is dictated to Schwann cells by the axon itself, based on the amount of Neuregulin I-type III exposed on its membrane. Peripheral axons are more important in determining the final myelination fate than central axons, and the implications for this difference in Schwann cells and oligodendrocytes are discussed. Interestingly, this choice is reversible during pathology, accounting for the remarkable plasticity of Schwann cells, and contributing to the regenerative potential of the peripheral nervous system. Radial sorting is the process by which Schwann cells choose larger axons to myelinate during development. This crucial morphogenetic step is a prerequisite for myelination and for differentiation of Remak fibers, and is arrested in human diseases due to mutations in genes coding for extracellular matrix and linkage molecules. In this review we will summarize progresses made in the last years by a flurry of reverse genetic experiments in mice and fish. This work revealed novel molecules that control radial sorting, and contributed unexpected ideas to our understanding of the cellular and molecular mechanisms that control radial sorting of axons.

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A Laminin-2, Dystroglycan, Utrophin Axis Is Required for Compartmentalization and Elongation of Myelin Segments

Cited by 64 publications

References 47 publications

Schwann cell spectrins modulate peripheral nerve myelination

Schwann cell spectrins modulate peripheral nerve myelination

Dynamic Regulation of Schwann Cell Enhancers after Peripheral Nerve Injury

How Schwann Cells Sort Axons

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