| 1. |
- Gustafsson, Renata, et al.
(author)
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Gene expression profiling of differentiating embryonic stem cells expressing dominant negative fibroblast growth factor receptor 2.
- 2007
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In: Matrix Biology. - : Elsevier BV. - 1569-1802 .- 0945-053X. ; 26, s. 197-205
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Journal article (peer-reviewed)abstract
- Embryonic stein (ES) cells are derived from the inner cell mass of the blastocyst and can be cultured as three-dimensional embryoid bodies (EBs) in which embryonic pregastrulation stages are faithfully mimicked. Fibroblast growth factor receptors (mainly FGFR2) are involved in the first differentiation events during early mammalian embryogenesis. It has been demonstrated that the presence of FGFR2 is a prerequisite for laminin-111 and collagen type IV synthesis and subsequently basement membrane formation in EBs. To identify genes that are influenced by FGFR signalling, we performed global gene expression profiling of differentiating EBs expressing dominant negative FGFR2 (dnFGFR2), acquiring an extensive catalogue of down- and up-regulated genes. We show a strong down-regulation of endodermal and basement membrane related genes, which strengthen the view that the FGFR signalling pathway is a main stimulator of basement membrane synthesis in EBs. We further present down-regulation of genes previously not linked to FGFR signalling, and in addition an active transcription of some mesodermal related genes in differentiating dnFGFR2 EBs.
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| 2. |
- Agrawal, Smriti, et al.
(author)
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Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis.
- 2006
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In: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 203:4, s. 1007-1019
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Journal article (peer-reviewed)abstract
- The endothelial cell monolayer of cerebral vessels and its basement membrane (BM) are ensheathed by the astrocyte endfeet, the leptomeningeal cells, and their associated parenchymal BM, all of which contribute to establishment of the blood–brain barrier (BBB). As a consequence of this unique structure, leukocyte penetration of cerebral vessels is a multistep event. In mouse experimental autoimmune encephalomyelitis (EAE), a widely used central nervous system inflammatory model, leukocytes first penetrate the endothelial cell monolayer and underlying BM using integrin β1-mediated processes, but mechanisms used to penetrate the second barrier defined by the parenchymal BM and glia limitans remain uninvestigated. We show here that macrophage-derived gelatinase (matrix metalloproteinase [MMP]-2 and MMP-9) activity is crucial for leukocyte penetration of the parenchymal BM. Dystroglycan, a transmembrane receptor that anchors astrocyte endfeet to the parenchymal BM via high affinity interactions with laminins 1 and 2, perlecan and agrin, is identified as a specific substrate of MMP-2 and MMP-9. Ablation of both MMP-2 and MMP-9 in double knockout mice confers resistance to EAE by inhibiting dystroglycan cleavage and preventing leukocyte infiltration. This is the first description of selective in situ proteolytic damage of a BBB-specific molecule at sites of leukocyte infiltration.
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| 4. |
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| 5. |
- Gawlik, Kinga, et al.
(author)
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Laminin {alpha}1 chain improves laminin {alpha}2 chain deficient peripheral neuropathy.
- 2006
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 15:18, s. 2690-2700
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Journal article (peer-reviewed)abstract
- Absence of laminin alpha2 chain leads to a severe form of congenital muscular dystrophy (MDC1A) associated with peripheral neuropathy. Hence, future therapies should be aimed at alleviating both muscle and neurological dysfunctions. Pre-clinical studies in animal models have mainly focused on ameliorating the muscle phenotype. Here we show that transgenic expression of laminin alpha1 chain in muscles and the peripheral nervous system of laminin alpha2 chain deficient mice reduced muscular dystrophy and largely corrected the peripheral nerve defects. The presence of laminin alpha1 chain in the peripheral nervous system resulted in near-normal myelination, restored Schwann cell basement membranes and improved rotarod performance. In summary, we postulate that laminin alpha1 chain is an excellent substitute for laminin alpha2 chain in multiple tissues and suggest that treatment with laminin alpha1 chain may be beneficial for MDC1A in humans.
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| 6. |
- Gawlik, Kinga, et al.
(author)
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Laminin alpha1 chain mediated reduction of laminin alpha2 chain deficient muscular dystrophy involves integrin alpha7beta1 and dystroglycan.
- 2006
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In: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 580:7, s. 1759-1765
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Journal article (peer-reviewed)abstract
- Transgenically introduced laminin (LN) α1 chain prevents muscular dystrophy in LNα2 chain deficient mice. We now report increased integrin α7Bβ1D synthesis in dystrophic LNα2 chain deficient muscle. Yet, immunofluorescence demonstrated a reduced expression of integrin α7B subunit at the sarcolemma. Transgenic expression of LNα1 chain reconstituted integrin α7B at the sarcolemma. Expression of α- and β-dystroglycan is enhanced in LNα2 chain deficient muscle and normalized by transgenic expression of LNα1 chain. We suggest that LNα1 chain in part ameliorates the development of LNα2 chain deficient muscular dystrophy by retaining the binding sites for integrin α7Bβ1D and α-dystroglycan, respectively.
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| 7. |
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| 8. |
- Gustafsson, Renata, et al.
(author)
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Expression of the novel gene Ened during mouse and Xenopus embryonic development.
- 2008
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In: International Journal of Developmental Biology. - : UPV/EHU Press. - 1696-3547 .- 0214-6282. ; 52:8, s. 1119-1122
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Journal article (peer-reviewed)abstract
- We have recently identified 1110032E23Rik as a down-regulated target gene in Fgf receptor-signalling-deficient mouse embryoid bodies. Here, we present the expression pattern of this novel gene, designated Ened (Expressed in Nerve and Epithelium during Development), in mouse and Xenopus laevis embryos. Murine Ened transcripts were first seen at E9.5 in the heart and the gastrointestinal tract. At later stages of gestation, expression could be found in the floor plate, peripheral nervous system, lens epithelium, skin, midline dorsal aorta, lung, kidney and testis. In Xenopus, the expression of the Ened orthologue displayed common RNA distribution in several ectodermal and mesodermal tissues, but also distinct expression in locations including the brain, notochord and blood islands. We suggest that Ened might be a novel target gene of the Fgfr signalling pathway during embryonic development, and that its expression could be modulated by the basement membrane component laminin-111.
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| 10. |
- Häger, Mattias, et al.
(author)
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Cib2 binds integrin a7Bb1D and is reduced in laminin a2 chain deficient muscular dystrophy
- 2008
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In: Journal of Biological Chemistry. - 1083-351X. ; 283:36, s. 24760-24769
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Journal article (peer-reviewed)abstract
- Mutations in the gene encoding laminin alpha 2 chain cause congenital muscular dystrophy type 1A. In skeletal muscle, laminin alpha 2 chain binds at least two receptor complexes: the dystrophin-glycoprotein complex and integrin alpha 7 beta 1. To gain insight into the molecular mechanisms underlying this disorder, we performed gene expression profiling of laminin alpha 2 chain-deficient mouse limb muscle. One of the down-regulated genes encodes a protein called Cib2 (calcium-and integrin-binding protein 2) whose expression and function is unknown. However, the closely related Cib1 has been reported to bind integrin alpha IIb and may be involved in outside-in-signaling in platelets. Since Cib2 might be a novel integrin alpha 7 beta 1-binding protein in muscle, we have studied Cib2 expression in the developing and adult mouse. Cib2 mRNA is mainly expressed in the developing central nervous system and in developing and adult skeletal muscle. In skeletal muscle, Cib2 colocalizes with the integrin alpha 7B subunit at the sarcolemma and at the neuromuscular and myotendinous junctions. Finally, we demonstrate that Cib2 is a calcium-binding protein that interacts with integrin alpha 7B beta 1D. Thus, our data suggest a role for Cib2 as a cytoplasmic effector of integrin alpha 7B beta 1D signaling in skeletal muscle.
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