β1-Integrin Signaling Mediates Premyelinating Oligodendrocyte Survival But Is Not Required for CNS Myelination and Remyelination

Benninger, Yves; Colognato, Holly; Thurnherr, Tina; Franklin, Robin J.M.; Leone, Dino P.; Atanasoski, Suzana; Nave, Klaus‐Armin; ffrench‐Constant, Charles; Suter, Ueli; Relvas, João B.

doi:10.1523/jneurosci.0444-06.2006

Cited by 103 publications

(114 citation statements)

References 42 publications

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“…3E). Similar defects in radial sorting are found in peripheral nerves of mice with Schwann cell-specific mutations affecting laminin isoforms (Chen and Strickland, 2003;Yu et al, 2005), the laminin receptor b1-integrin (Feltri et al, 2002;Nodari et al, 2007), the tyrosine kinase FAK, integrin-linked kinase and downstream signaling components in Schwann cells (Benninger et al, 2006;Grove et al, 2007;Nodari et al, 2007;Pereira et al, 2009). Although Schwann cells in Gpr126-/-mutant mice eventually recover and sort axons, these early phenotypic similarities suggest a possible connection between Gpr126 and signaling between laminins and their integrin receptors.…”

Section: Discussionmentioning

confidence: 58%

Gpr126 is essential for peripheral nerve development and myelination in mammals

et al. 2011

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SUMMARYIn peripheral nerves, Schwann cells form the myelin sheath that insulates axons and allows rapid propagation of action potentials. Although a number of regulators of Schwann cell development are known, the signaling pathways that control myelination are incompletely understood. In this study, we show that Gpr126 is essential for myelination and other aspects of peripheral nerve development in mammals. A mutation in Gpr126 causes a severe congenital hypomyelinating peripheral neuropathy in mice, and expression of differentiated Schwann cell markers, including Pou3f1, Egr2, myelin protein zero and myelin basic protein, is reduced. Ultrastructural studies of Gpr126-/-mice showed that axonal sorting by Schwann cells is delayed, Remak bundles (non-myelinating Schwann cells associated with small caliber axons) are not observed, and Schwann cells are ultimately arrested at the promyelinating stage. Additionally, ectopic perineurial fibroblasts form aberrant fascicles throughout the endoneurium of the mutant sciatic nerve. This analysis shows that Gpr126 is required for Schwann cell myelination in mammals, and defines new roles for Gpr126 in axonal sorting, formation of mature non-myelinating Schwann cells and organization of the perineurium.

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Section: Discussionmentioning

confidence: 58%

Gpr126 is essential for peripheral nerve development and myelination in mammals

et al. 2011

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“…Mice homozygous for the Cdc42 floxed allele (Cdc42 lox/lox ) were crossed with mice heterozygous for the Cdc42 floxed allele, which expressed the Cre recombinase under the control of the CNPase (Cnp-Cre ϩ Cdc42 lox/wt ) (Genoud et al, 2002;Lappe-Siefke et al, 2003;Saher et al, 2005) (Soriano, 1999) into control and mutant mice. Cnp-Cre is active in Ͼ70% of all oligodendroglial cells (Benninger et al, 2006). Genotypes were determined by performing PCR on genomic DNA.…”

Section: Methodsmentioning

confidence: 99%

“…Oligodendrocyte progenitor cells (OPCs) were purified from mixed glial cultures (McCarthy and de Vellis, 1980) and differentiated on extracellular matrix substrates (Relvas et al, 2001). For 5-bromo-4-chloro-3-indolyl-␤-D-galactopyranoside (X-gal) staining, cells were fixed in 2% formaldehyde and 0.2% glutaraldehyde in PBS for 7 min and stained in X-gal staining solution [5 mM K 3 [Fe(CN) 6 ], 5 mM K 4 [Fe(CN) 6 ], 2 mM MgCl 2 , and 1 mg/ml of X-gal (Calbiochem, La Jolla, CA) in PBS] overnight at 37°C as described previously (Benninger et al, 2006). Proliferation was measured with the 5-Bromo-2Ј-Deoxyuridine Labeling and Detection Kit I (Roche Diagnostics) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

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Cdc42 and Rac1 Signaling Are Both Required for and Act Synergistically in the Correct Formation of Myelin Sheaths in the CNS

Thurnherr¹,

Benninger²,

Wu³

et al. 2006

J. Neurosci.

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125

123

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The formation of myelin sheaths in the CNS is the result of a complex series of events involving oligodendrocyte progenitor cell (OPC) proliferation, directed migration, and the morphological changes associated with axon ensheathment and myelination. To examine the role of Rho GTPases in oligodendrocyte biology, we have used a conditional tissue-specific gene-targeting approach. Ablation of Cdc42 in cells of the oligodendrocyte lineage did not affect OPC proliferation, directed migration, or in vitro differentiation, but it led to the formation of a unique and stage-specific myelination phenotype. This was characterized by the extraordinary enlargement of the inner tongue of the oligodendrocyte process and concomitant formation of a myelin outfolding as a result of abnormal accumulation of cytoplasm in this region. Ablation of Rac1 also resulted in the abnormal accumulation of cytoplasm in the inner tongue of the oligodendrocyte process, and we provide genetic evidence that rac1 synergizes with cdc42 in a gene dosage-dependent way to regulate myelination.

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“…In fact, genetic studies addressing the function of β1 integrins in oligodendrocytes have led to contradictory results. Whereas oligodendrocyte-specific expression of a dominantnegative (DN) β1 integrin in a transgenic mouse model was associated with CNS hypomyelination (Camara et al, 2009;Lee et al, 2006), conditional ablation of a floxed allele of the β1 gene (Itgb1) in oligodendrocytes using a CNPase-Cre (Cnp-CreMouse Genome Informatics) driver caused no myelination defects (Benninger et al, 2006). The interpretation of these experiments is complex, as DN β1 integrins can also ectopically activate integrin signaling (Lukashev et al, 1994), and CNPase-Cre induces recombination in only a subset of oligodendrocytes by P0 (Benninger et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

β1 integrins are required for normal CNS myelination and promote AKT-dependent myelin outgrowth

et al. 2009

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Oligodendrocytes in the central nervous system (CNS) produce myelin sheaths that insulate axons to ensure fast propagation of action potentials. β1 integrins regulate the myelination of peripheral nerves, but their function during the myelination of axonal tracts in the CNS is unclear. Here we show that genetically modified mice lacking β1 integrins in the CNS present a deficit in myelination but no defects in the development of the oligodendroglial lineage. Instead, in vitro data show that β1 integrins regulate the outgrowth of myelin sheaths. Oligodendrocytes derived from mutant mice are unable to efficiently extend myelin sheets and fail to activate AKT (also known as AKT1), a kinase that is crucial for axonal ensheathment. The inhibition of PTEN, a negative regulator of AKT, or the expression of a constitutively active form of AKT restores myelin outgrowth in cultured β1-deficient oligodendrocytes. Our data suggest that β1 integrins play an instructive role in CNS myelination by promoting myelin wrapping in a process that depends on AKT.

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β1-Integrin Signaling Mediates Premyelinating Oligodendrocyte Survival But Is Not Required for CNS Myelination and Remyelination

Cited by 103 publications

References 42 publications

Gpr126 is essential for peripheral nerve development and myelination in mammals

Gpr126 is essential for peripheral nerve development and myelination in mammals

Cdc42 and Rac1 Signaling Are Both Required for and Act Synergistically in the Correct Formation of Myelin Sheaths in the CNS

β1 integrins are required for normal CNS myelination and promote AKT-dependent myelin outgrowth

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