Assessing the Role of the Cadherin/Catenin Complex at the Schwann Cell–Axon Interface and in the Initiation of Myelination

Lewallen, Kathryn A.; Shen, Yu‐Chu; Torre, Asia R. De La; Ng, Benjamin; Meijer, Dies; Chan, Jonah R.

doi:10.1523/jneurosci.4345-10.2011

Cited by 61 publications

(60 citation statements)

References 39 publications

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“…That the Smad3 −/− phenotype is the more severe might be attributable to complete versus partial ablation of Tgfβ/Activin Smad-dependent signaling. The compensation seen in both genotypes also follows a precedent in other models displaying deficits in oligodendrocyte development and/or myelination (Montag et al, 1994;Larsen et al, 2006;Lewallen et al, 2011), although recovery is not a universal outcome (Meyerheim et al, 2004;Nolan et al, 2005;Emery et al, 2009). Our findings are also compatible with data from previous studies in mutants for MAP kinase components (Schwammenthal et al, 2004;Fyffe-Maricich et al, 2011).…”

Section: Smad3 Activity In Olig2supporting

confidence: 91%

“…Multiple pathways contribute to the generation of myelinating cells, and a strong precedent exists for recovery of myelination in mutants showing deficits in progenitor development (Montag et al, 1994;Larsen et al, 2006;Lewallen et al, 2011). Postnatally in Inhbb −/− spinal cords, the fraction of apoptotic Olig2 + cells remained slightly but significantly increased, and the fraction of cycling Ki67 + Olig2 + cells was marginally (but significantly) raised (Fig.…”

Section: Co-treatment With Tgfβ1 Plus Actb Enhances Myelin Formation mentioning

confidence: 94%

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Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

et al. 2014

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In the embryonic CNS, development of myelin-forming oligodendrocytes is limited by bone morphogenetic proteins, which constitute one arm of the transforming growth factor-β (Tgfβ) family and signal canonically via Smads 1/5/8. Tgfβ ligands and Activins comprise the other arm and signal via Smads 2/3, but their roles in oligodendrocyte development are incompletely characterized. Here, we report that Tgfβ ligands and activin B (ActB) act in concert in the mammalian spinal cord to promote oligodendrocyte generation and myelination. In mouse neural tube, newly specified oligodendrocyte progenitors (OLPs) are first exposed to Tgfβ ligands in isolation, then later in combination with ActB during maturation. In primary OLP cultures, Tgfβ1 and ActB differentially activate canonical Smad3 and non-canonical MAP kinase signaling. Both ligands enhance viability, and Tgfβ1 promotes proliferation while ActB supports maturation. Importantly, co-treatment strongly activates both signaling pathways, producing an additive effect on viability and enhancing both proliferation and differentiation such that mature oligodendrocyte numbers are substantially increased. Co-treatment promotes myelination in OLPneuron co-cultures, and maturing oligodendrocytes in spinal cord white matter display strong Smad3 and MAP kinase activation. In spinal cords of ActB-deficient Inhbb −/− embryos, apoptosis in the oligodendrocyte lineage is increased and OLP numbers transiently reduced, but numbers, maturation and myelination recover during the first postnatal week. Smad3 −/− mice display a more severe phenotype, including diminished viability and proliferation, persistently reduced mature and immature cell numbers, and delayed myelination. Collectively, these findings suggest that, in mammalian spinal cord, Tgfβ ligands and ActB together support oligodendrocyte development and myelin formation.

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Section: Smad3 Activity In Olig2supporting

confidence: 91%

Section: Co-treatment With Tgfβ1 Plus Actb Enhances Myelin Formation mentioning

confidence: 94%

Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

et al. 2014

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“…S8), although we cannot exclude the possibility that spectrins function downstream of these molecules during myelination. Indeed, N-cadherin and β-catenin are involved in establishing Schwann cell polarity and the timely initiation of myelination (19), and α-catenin, a binding partner of β-catenin, directly interacts with the αII and βII spectrin complex (20). Taken together, these findings strongly support the conclusion that loss of the spectrinbased cytoskeleton in Schwann cells impairs multiple mechanisms that contribute to proper PNS myelination.…”

Section: The Spectrin Cytoskeleton Is Polarized In Premyelinating Schsupporting

confidence: 58%

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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“…An intricate signalling network that involves between neurons and SCs controls nerve regeneration via signalling molecules such as neurotrophic factors and adhesion molecules [1,2]. Some studies have demonstrated the important role of the Ca 2+ -dependent glycoprotein neural cadherin (Ncadherin) in the growth and guidance of axons, as well as in cell adhesion (SC-SC and SC-axon contacts) and myelination [3][4][5][6][7][8][9]. These interactions are essential for SCs to form the bands of Bungner that bridge the injury site to provide an adhesive substrate for regrowing axons [1].…”

Section: Introductionmentioning

confidence: 99%

N-cadherin expression is regulated by UTP in schwannoma cells

Martiáñez

Lamarca

Casals

et al. 2012

Purinergic Signalling

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Schwann cells (SCs) are peripheral myelinating glial cells that express the neuronal Ca 2+ -dependent cell adhesion molecule, neural cadherin (N-cadherin). Ncadherin is involved in glia-glia and axon-glia interactions and participates in many key events, which range from the control of axonal growth and guidance to synapse formation and plasticity. Extracellular UTP activates P2Y purinergic receptors and exerts short-and long-term effects on several tissues to promote wound healing. Nevertheless, the contribution of P2Y receptors in peripheral nervous system functions is not completely understood. The current study demonstrated that UTP induced a dose-and timedependent increase in N-cadherin expression in SCs. Furthermore, N-cadherin expression was blocked by the P2 purinoceptor antagonist suramin. The increased N-cadherin expression induced by UTP was mediated by phosphorylation of mitogen-activated protein kinases (MAPKs), such as Jun N-terminal kinase, extracellular-regulated kinase and p38 kinase. Moreover, the Rho kinase inhibitor Y27632, the phospholipase C inhibitor U73122 and the protein kinase C inhibitor calphostin C attenuated the UTP-induced activation of MAPKs significantly. Extracellular UTP also modulated increased in the expression of the early transcription factors c-Fos and c-Jun. We also demonstrated that the region of the N-cadherin promoter between nucleotide positions −3698 and −2620, which contained one activator protein-1-binding site, was necessary for UTP-induced gene expression. These results suggest a novel role for P2Y purinergic receptors in the regulation of N-cadherin expression in SCs.

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Assessing the Role of the Cadherin/Catenin Complex at the Schwann Cell–Axon Interface and in the Initiation of Myelination

Cited by 61 publications

References 39 publications

Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination

Schwann cell spectrins modulate peripheral nerve myelination

N-cadherin expression is regulated by UTP in schwannoma cells

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