| 1. |
- Gustafsson, Renata, et al.
(författare)
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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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Ingår i: Matrix Biology. - : Elsevier BV. - 1569-1802 .- 0945-053X. ; 26, s. 197-205
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Tidskriftsartikel (refereegranskat)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. |
- Olsson, Magnus, et al.
(författare)
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Nulp1, a novel basic helix-loop-helix protein expressed broadly during early embryonic organogenesis and prominently in developing dorsal root ganglia.
- 2002
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Ingår i: Cell and Tissue Research. - : Springer Science and Business Media LLC. - 1432-0878 .- 0302-766X. ; 308:3, s. 361-370
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Tidskriftsartikel (refereegranskat)abstract
- The basic helix-loop-helix (bHLH) proteins control differentiation and development of a variety of organs. We have isolated the complementary DNA (cDNA) of a novel class of bHLH transcription factors. The previously uncharacterized bHLH messenger RNA (mRNA) was identified by RNA fingerprinting by comparing embryonic and adult mRNA. The reading frame sequence predicts a new class of bHLH family. Northern blotting of embryonic stages demonstrated a 3.2-kb transcript present in several embryonic tissues, including kidney, brain, heart, and lung, in a fashion confirmatory with the RNA-fingerprinting data. In situ hybridization of cryosections detected strong signals in the dorsal root ganglia of 14-day-old mouse embryos (E14). Transient transfection of human embryonic kidney cells with Nulp1-EGFP demonstrated nuclear localization. The complex expression pattern and unique protein sequence, including an acidic amino terminal and putative transcription activation domain, suggests that Nulp1 may have a distinct role in embryonic development of many organs, including the adult brain.
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| 3. |
- Agrawal, Smriti, et al.
(författare)
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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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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 203:4, s. 1007-1019
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Tidskriftsartikel (refereegranskat)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. |
- Carmignac, Virginie, et al.
(författare)
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Autophagy is increased in laminin {alpha}2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A.
- 2011
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:24, s. 4891-4902
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Tidskriftsartikel (refereegranskat)abstract
- Congenital muscular dystrophy caused by laminin α2 chain deficiency (also known as MDC1A) is a severe and incapacitating disease, characterized by massive muscle wasting. The ubiquitin-proteasome system plays a major role in muscle wasting and we recently demonstrated that increased proteasomal activity is a feature of MDC1A. The autophagy-lysosome pathway is the other major system involved in degradation of proteins and organelles within the muscle cell. However, it remains to be determined if the autophagy-lysosome pathway is dysregulated in muscular dystrophies, including MDC1A. Using the dy(3K)/dy(3K) mouse model of laminin α2 chain deficiency and MDC1A patient muscle, we show here that expression of autophagy-related genes is upregulated in laminin α2 chain-deficient muscle. Moreover, we found that autophagy inhibition significantly improves the dystrophic dy(3K)/dy(3K) phenotype. In particular, we show that systemic injection of 3-methyladenine (3-MA) reduces muscle fibrosis, atrophy, apoptosis and increases muscle regeneration and muscle mass. Importantly, lifespan and locomotive behavior were also greatly improved. These findings indicate that enhanced autophagic activity is pathogenic and that autophagy inhibition holds a promising therapeutic potential in the treatment of MDC1A.
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| 5. |
- Carmignac, Virginie, et al.
(författare)
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Cell-matrix interactions in muscle disease.
- 2012
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417. ; 226, s. 200-218
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Tidskriftsartikel (refereegranskat)abstract
- The extracellular matrix provides a solid scaffold and signals to cells through extracellular matrix receptors. The cell-matrix interactions are crucial for normal biological processes and when disrupted they may lead to pathological processes. In particular, the biological importance of extracellular matrix-cell membrane-cytoskeleton interactions in skeletal muscle is accentuated by the number of inherited muscle diseases caused by mutations in proteins conferring these interactions. In this review we will introduce laminins, collagens, dystroglycan, integrins, dystrophin and sarcoglycans. Mutations in corresponding genes cause various forms of muscular dystrophy. The muscle disorders will be presented as well as advances toward development of treatment. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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| 6. |
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| 7. |
- Carmignac, Virginie, et al.
(författare)
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Proteasome Inhibition Improves the Muscle of Laminin {alpha}2 Chain Deficient Mice.
- 2011
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:3, s. 541-552
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Tidskriftsartikel (refereegranskat)abstract
- Muscle atrophy, a significant characteristic of congenital muscular dystrophy with laminin α2 chain deficiency (also known as MDC1A), occurs by a change in the normal balance between protein synthesis and protein degradation. The ubiquitin-proteasome system plays a key role in protein degradation in skeletal muscle cells. In order to identify new targets for drug therapy against MDC1A, we have investigated whether increased proteasomal degradation is a feature of MDC1A. Using the generated dy(3K)/dy(3K) mutant mouse model of MDC1A, we studied the expression of members of the ubiquitin-proteasome pathway in laminin α2 chain deficient muscle and we treated dy(3K)/dy(3K) mice with the proteasome inhibitor MG-132. We show that members of the ubiquitin-proteasome system are upregulated and that the global ubiquitination of proteins is raised in dystrophic limb muscles. Also, phosphorylation of Akt is diminished in diseased muscles. Importantly, proteasome inhibition significantly improves the dystrophic dy(3K)/dy(3K) phenotype. Specifically, treatment with MG-132 increases lifespan, enhances locomotive activity, enlarges muscle fiber diameter, reduces fibrosis, restores Akt phosphorylation and decreases apoptosis. These studies promote better understanding of the disease process in mice and could lead to a drug therapy for MDC1A patients.
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| 8. |
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| 9. |
- Durbeej-Hjalt, Madeleine
(författare)
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Laminin-α2 Chain-Deficient Congenital Muscular Dystrophy: Pathophysiology and Development of Treatment.
- 2015
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Ingår i: Current Topics in Membranes. - : Elsevier. - 1063-5823. ; 76, s. 31-60
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Tidskriftsartikel (refereegranskat)abstract
- Laminin-211 is a major constituent of the skeletal muscle basement membrane. It stabilizes skeletal muscle and influences signal transduction events from the myomatrix to the muscle cell. Mutations in the gene encoding the α2 chain of laminin-211 lead to congenital muscular dystrophy type 1A (MDC1A), a life-threatening disease characterized by severe hypotonia, progressive muscle weakness, and joint contractures. Common complications include severely impaired motor ability, respiratory failure, and feeding difficulties. Several adequate animal models for laminin-α2 chain deficiency exist and analyses of different MDC1A mouse models have led to a significant improvement in our understanding of MDC1A pathogenesis. Importantly, the animal models have been indispensable tools for the preclinical development of new therapeutic approaches for laminin-α2 chain deficiency, highlighting a number of important disease driving mechanisms that can be targeted by pharmacological approaches. In this chapter, I will describe laminin-211 and discuss the cellular and molecular pathophysiology of MDC1A as well as progression toward development of treatment.
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| 10. |
- Durbeej-Hjalt, Madeleine
(författare)
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Laminins.
- 2010
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Ingår i: Cell and Tissue Research. - : Springer Science and Business Media LLC. - 1432-0878 .- 0302-766X. ; 339, s. 259-268
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Tidskriftsartikel (refereegranskat)abstract
- Laminins are cell adhesion molecules that comprise a family of glycoproteins found predominantly in basement membranes, which are the thin sheets of extracellular matrix that underlie epithelial and endothelial cells and surround muscle cells, Schwann cells, and fat cells. Many laminins self-assemble to form networks that remain in close association with cells through interactions with cell surface receptors. Laminins are vital for many physiological functions. They are essential for early embryonic development and organogenesis and have crucial functions in several tissues including muscle, nerve, skin, kidney, lung, and the vasculature. A great wealth of data on laminins is available, and an in-depth description is not attempted here. In this review, I will instead provide a snapshot of laminin structure, tissue distribution, and interactions with other matrix molecules and receptors and briefly describe laminin mutations in mice and humans. Several illuminating and timely reviews are cited that can be consulted for references to original articles and more detailed information concerning laminins.
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| 11. |
- Elowsson, Linda, et al.
(författare)
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Evaluation of macroporous blood and plasma scaffolds for skeletal muscle tissue engineering
- 2013
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Ingår i: Biomaterials Science. - : Royal Society of Chemistry (RSC). - 2047-4830 .- 2047-4849. ; 1:4, s. 402-410
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Tidskriftsartikel (refereegranskat)abstract
- The field of tissue engineering has a growing need for suitable scaffold materials to become attractive as a clinical therapy. To use a completely autologous construct to repair a damaged or diseased tissue is an appealing thought. As a model system, two types of scaffolds were prepared from biological fluids: blood and plasma. The prepared scaffolds formed a macroporous structure with elastic mechanical properties that were further evaluated with myoblast cell line (C2C12) cultivation and transplantation into mouse skeletal muscle. The cells were found to attach, proliferate, and migrate through all the different scaffolds. Moreover, the cells underwent myogenic differentiation, showing typical cell morphology aligned in a parallel fashion. An increased level of myogenin mRNA was found with the time of culture. Furthermore, myogenic markers MyoD1, desmin, myogenin and myosin, as well as beta-dystroglycan and the laminin alpha 2 chain, were found to be expressed. In vivo data indicated that the scaffolds degraded and were replaced with regenerated muscle fibres. We conclude that the two types of macroporous scaffolds based on blood or plasma have potential in the field of skeletal muscle tissue engineering.
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| 12. |
- Elowsson, Linda, et al.
(författare)
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Porous protein-based scaffolds prepared through freezing as potential scaffolds for tissue engineering.
- 2012
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Ingår i: Journal of Materials Science: Materials in Medicine. - : Springer Science and Business Media LLC. - 1573-4838 .- 0957-4530. ; 23:10, s. 2489-2498
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Tidskriftsartikel (refereegranskat)abstract
- Successful tissue engineering with the aid of a polymer scaffold offers the possibility to produce a larger construct and to mould the shape after the defect. We investigated the use of cryogelation to form protein-based scaffolds through different types of formation mechanisms; enzymatic crosslinking, chemical crosslinking, and non-covalent interactions. Casein was found to best suited for enzymatic crosslinking, gelatin for chemical crosslinking, and ovalbumin for non-covalent interactions. Fibroblasts and myoblasts were used to evaluate the cryogels for tissue engineering purposes. The stability of the cryogels over time in culture differed depending on formation mechanism. Casein cryogels showed best potential to be used in skeletal tissue engineering, whereas gelatin cryogels would be more suitable for compliable soft tissues even though it also seemed to support a myogenic phenotype. Ovalbumin cryogels would be better suited for elastic tissues with faster regeneration properties due to its faster degradation time. Overall, the cryogelation technique offers a fast, cheap and reproducible way of creating porous scaffolds from proteins without the use of toxic compounds.
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| 13. |
- Fontes Oliveira, Cibely, et al.
(författare)
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Effects of metformin on congenital muscular dystrophy type 1A disease progression in mice: a gender impact study
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322.
-
Tidskriftsartikel (refereegranskat)abstract
- Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe muscle disorder with complex underlying pathogenesis. We have previously employed profiling techniques to elucidate molecular patterns and demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Thus, we hypothesize that skeletal muscle metabolism may be a promising pharmacological target to improve muscle function in LAMA2-CMD. Here, we have investigated whether the multifunctional medication metformin could be used to reduce disease in the dy2J/dy2J mouse model of LAMA2-CMD. First, we show gender disparity for several pathological hallmarks of LAMA2-CMD. Second, we demonstrate that metformin treatment significantly increases weight gain and energy efficiency, enhances muscle function and improves skeletal muscle histology in female dy2J/dy2J mice (and to a lesser extent in dy2J/dy2J males). Thus, our current data suggest that metformin may be a potential future supportive treatment that improves many of the pathological characteristics of LAMA2-CMD.
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| 14. |
- Gawlik, Kinga, et al.
(författare)
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Deletion of integrin α7 subunit does not aggravate the phenotype of laminin α2 chain-deficient mice.
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- Laminin-211 is a major constituent of the skeletal muscle basement membrane, exerting its biological functions by binding to cell surface receptors integrin α7β1 and dystroglycan (the latter is part of the dystrophin-glycoprotein complex). The importance of these molecules for normal muscle function is underscored by the fact that their respective deficiency leads to different forms of muscular dystrophy with different severity in humans and animal models. We recently demonstrated that laminin α2 chain and members of the dystrophin-glycoprotein complex have overlapping but non-redundant roles despite being part of the same adhesion complex. To analyse whether laminin-211 and integrin α7 subunit have non-redundant functions we generated mice deficient in laminin α2 chain and integrin α7 subunit (dy(3K)/itga7). We show that lack of both molecules did not exacerbate the severe phenotype of laminin α2-chain deficient animals. They displayed the same weight, survival and dystrophic pattern of muscle biopsy, with similar degree of inflammation and fibrosis. These data suggest that laminin-211 and integrin α7β1 have intersecting roles in skeletal muscle.
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| 15. |
- Gawlik, Kinga, et al.
(författare)
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Distinct roles for laminin globular domains in laminin alpha1 chain mediated rescue of murine laminin alpha2 chain deficiency.
- 2010
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Laminin alpha2 chain mutations cause congenital muscular dystrophy with dysmyelination neuropathy (MDC1A). Previously, we demonstrated that laminin alpha1 chain ameliorates the disease in mice. Dystroglycan and integrins are major laminin receptors. Unlike laminin alpha2 chain, alpha1 chain binds the receptors by separate domains; laminin globular (LG) domains 4 and LG1-3, respectively. Thus, the laminin alpha1 chain is an excellent tool to distinguish between the roles of dystroglycan and integrins in the neuromuscular system. METHODOLOGY/PRINCIPAL FINDINGS: Here, we provide insights into the functions of laminin alpha1LG domains and the division of their roles in MDC1A pathogenesis and rescue. Overexpression of laminin alpha1 chain that lacks the dystroglycan binding LG4-5 domains in alpha2 chain deficient mice resulted in prolonged lifespan and improved health. Importantly, diaphragm and heart muscles were corrected, whereas limb muscles were dystrophic, indicating that different muscles have different requirements for LG4-5 domains. Furthermore, the regenerative capacity of the skeletal muscle did not depend on laminin alpha1LG4-5. However, this domain was crucial for preventing apoptosis in limb muscles, essential for myelination in peripheral nerve and important for basement membrane assembly. CONCLUSIONS/SIGNIFICANCE: These results show that laminin alpha1LG domains and consequently their receptors have disparate functions in the neuromuscular system. Understanding these interactions could contribute to design and optimization of future medical treatment for MDC1A patients.
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| 16. |
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| 17. |
- Gawlik, Kinga I., et al.
(författare)
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Potent pro-inflammatory and profibrotic molecules, osteopontin and galectin-3, are not major disease modulators of laminin α2 chaindeficient muscular dystrophy
- 2017
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- A large number of human diseases are caused by chronic tissue injury with fibrosis potentially leading to organ failure. There is a need for more effective anti-fibrotic therapies. Congenital muscular dystrophy type 1A (MDC1A) is a devastating form of muscular dystrophy caused by laminin α2 chaindeficiency. It is characterized with early inflammation and build-up of fibrotic lesions, both in patients and MDC1A mouse models (e.g. dy3K/dy3K). Despite the enormous impact of inflammation on tissue remodelling in disease, the inflammatory response in MDC1A has been poorly described. Consequently, a comprehensive understanding of secondary mechanisms (impaired regeneration, enhanced fibrosis) leading to deterioration of muscle phenotype in MDC1A is missing. We have monitored inflammatory processes in dy3K/dy3K muscle and created mice deficient in laminin α2 chain and osteopontin or galectin-3, two pro-inflammatory and pro-fibrotic molecules drastically increased in dystrophic muscle. Surprisingly, deletion of osteopontin worsened the phenotype of dy3K/dy3K mice and loss of galectin-3 did not reduce muscle pathology. Our results indicate that osteopontin could even be a beneficial immunomodulator in MDC1A. This knowledge is essential for the design of future therapeutic interventions for muscular dystrophies that aim at targeting inflammation, especially that osteopontin inhibition has been suggested for Duchenne muscular dystrophy therapy.
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| 18. |
- Gawlik, Kinga, et al.
(författare)
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Laminin {alpha}1 chain improves laminin {alpha}2 chain deficient peripheral neuropathy.
- 2006
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 15:18, s. 2690-2700
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Tidskriftsartikel (refereegranskat)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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| 19. |
- Gawlik, Kinga, et al.
(författare)
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Laminin {alpha}1 chain reduces muscular dystrophy in laminin {alpha}2 chain deficient mice.
- 2004
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 13:16, s. 1775-1784
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Tidskriftsartikel (refereegranskat)abstract
- Laminin (LN) {alpha}2 chain deficiency in humans and mice leads to severe forms of congenital muscular dystrophy (CMD). Here, we investigated whether LN{alpha}1 chain in mice can compensate for the absence of LN{alpha}2 chain and prevent the development of muscular dystrophy. We generated mice expressing a LN{alpha}1 chain transgene in skeletal muscle of LN{alpha}2 chain deficient mice. LN{alpha}1 is not normally expressed in muscle, but the transgenically produced LN{alpha}1 chain was incorporated into muscle basement membranes, and normalized the compensatory changes of expression of certain other laminin chains ({alpha}4, ß2). In 4-month-old mice, LN{alpha}1 chain could fully prevent the development of muscular dystrophy in several muscles, and partially in others. The LN{alpha}1 chain transgene not only reversed the appearance of histopathological features of the disease to a remarkable degree, but also greatly improved health and longevity of the mice. Correction of LN{alpha}2 chain deficiency by LN{alpha}1 chain may serve as a paradigm for gene therapy of CMD in patients.
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| 20. |
- Gawlik, Kinga, et al.
(författare)
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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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Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 580:7, s. 1759-1765
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Tidskriftsartikel (refereegranskat)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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| 21. |
- Gawlik, Kinga, et al.
(författare)
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Loss of Dystrophin and β-Sarcoglycan, Respectively, Significantly Exacerbates the Phenotype of Laminin α2 Chain-Deficient Animals.
- 2014
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 184:3, s. 740-752
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Tidskriftsartikel (refereegranskat)abstract
- The adhesion molecule laminin α2 chain interacts with the dystrophin-glycoprotein complex, contributes to normal muscle function, and protects skeletal muscles from damage. Complete loss of the laminin α2 chain in mice results in a severe muscular dystrophy phenotype and death at approximately 3 weeks of age. However, it is not clear if the remaining members of the dystrophin-glycoprotein complex further protect laminin α2 chain-deficient skeletal muscle fibers from degeneration. Hence, we generated mice deficient in laminin α2 chain and dystrophin (dy(3K)/mdx) and mice devoid of laminin α2 chain and β-sarcoglycan (dy(3K)/Sgcb). Severe muscular dystrophy and a lack of nourishment inevitably led to massive muscle wasting and death in double-knockout animals. The dy(3K)/Sgcb mice were generally more severely affected than dy(3K)/mdx mice. However, both double-knockout strains displayed exacerbated muscle degeneration, inflammation, fibrosis, and reduced life span (5 to 13 days) compared with single-knockout animals. However, neither extraocular nor cardiac muscle was affected in double-knockout animals. Our results suggest that, although laminin α2 chain, dystrophin, and β-sarcoglycan are all part of the same adhesion complex, they have complementary, but nonredundant, roles in maintaining sarcolemmal integrity and protecting skeletal muscle fibers from damage. Moreover, the double-knockout mice could potentially serve as models in which to study extremely aggressive muscle-wasting conditions.
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| 22. |
- Gawlik, Kinga, et al.
(författare)
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Skeletal muscle laminin and MDC1A: pathogenesis and treatment strategies.
- 2011
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Ingår i: Skeletal Muscle. - : Springer Science and Business Media LLC. - 2044-5040. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- Laminin-211 is a cell-adhesion molecule that is strongly expressed in the basement membrane of skeletal muscle. By binding to the cell surface receptors dystroglycan and integrin α7β1, laminin-211 is believed to protect the muscle fiber from damage under the constant stress of contractions, and to influence signal transmission events. The importance of laminin-211 in skeletal muscle is evident from merosin-deficient congenital muscular dystrophy type 1A (MDC1A), in which absence of the α2 chain of laminin-211 leads to skeletal muscle dysfunction. MDC1A is the commonest form of congenital muscular dystrophy in the European population. Severe hypotonia, progressive muscle weakness and wasting, joint contractures and consequent impeded motion characterize this incurable disorder, which causes great difficulty in daily life and often leads to premature death. Mice with laminin α2 chain deficiency have analogous phenotypes, and are reliable models for studies of disease mechanisms and potential therapeutic approaches. In this review, we introduce laminin-211 and describe its structure, expression pattern in developing and adult muscle and its receptor interactions. We will also discuss the molecular pathogenesis of MDC1A and advances toward the development of treatment.
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| 23. |
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| 24. |
- Gawlik, Kinga, et al.
(författare)
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Transgenic Expression of Laminin α1 Chain Does Not Prevent Muscle Disease in the mdx Mouse Model for Duchenne Muscular Dystrophy.
- 2011
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 178:4, s. 1728-1737
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Tidskriftsartikel (refereegranskat)abstract
- Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder, and one of the most frequently encountered, but one for which there is as yet no treatment. Laminin-111 protein therapy was recently shown to be a promising approach to prevent muscle disease in the mdx mouse model of DMD. The present study demonstrated that transgenic expression of laminin α1 chain in mdx animals, resulting in laminin-111 heterotrimer formation in mdx muscle, does not improve the dystrophic phenotype. The mdx mice overexpressing laminin-111 (mdxLMα1) display features of mdx littermates: dystrophic pattern of muscle biopsy, elevated creatine kinase levels, reduced muscle strength, and decreased sarcolemmal integrity. Increased expression of integrin α7 is not beneficial for mdxLMα1 muscle, and components of the dystrophin-glycoprotein complex are not restored at the sarcolemma on laminin-111 overexpression. In summary, further studies are needed to verify the functionality of laminin-111 protein therapy in DMD and to describe the molecular events resulting from this approach.
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| 25. |
- Gawlik, Kinga, et al.
(författare)
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Transgenic overexpression of laminin 1 chain in laminin 2 chain-deficient mice rescues the disease throughout the lifespan
- 2010
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Ingår i: Muscle and Nerve. - : Wiley. - 0148-639X .- 1097-4598. ; 42:1, s. 30-37
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Tidskriftsartikel (refereegranskat)abstract
- Several approaches to treat laminin alpha 2 chain-deficient congenital muscular dystrophy (MDC1A) in mouse models have been undertaken. Most have shown promising results in young animals. However, older animals have only been characterized to some extent. Herein we analyze the lifespan of laminin alpha 2 chain deficient mice with transgenic overexpression of laminin alpha 1 chain. Further outcome measures included internalized myonuclei, heart fibrosis, grip strength, and serum creatine kinase activity. We show that laminin alpha 2-chain-deficient animals that overexpress laminin alpha 1 chain survive to up to 1.5-2 years of age. Furthermore, they displayed improved skeletal and heart muscle morphology, near-normal muscle strength, and normalized creatine kinase levels. Such an improvement of the dystrophic phenotype that persists to old age has not been previously demonstrated in mice. Our findings hold promise with regard to the efficient treatment of MDC1A patients in the future. Muscle Nerve 42: 30-37, 2010
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| 26. |
- Gu, Yuchen, et al.
(författare)
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Characterization of bone marrow laminins and identification of alpha5-containing laminins as adhesive proteins for multipotent hematopoietic FDCP-Mix cells
- 1999
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Ingår i: Blood. - 0006-4971. ; 93:8, s. 2533-2542
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Tidskriftsartikel (refereegranskat)abstract
- Laminins are extracellular matrix glycoproteins that influence the phenotype and functions of many types of cells. Laminins are heterotrimers composed of alpha, beta, and gamma polypeptides. So far five alpha, three beta, and two gamma polypeptide chains, and 11 variants of laminins have been proposed. Laminins interact in vitro with mature blood cells and malignant hematopoietic cells. Most studies have been performed with laminin-1 (alpha1beta1gamma1), and its expression in bone marrow is unclear. Employing an antiserum reacting with most laminin isoforms, we found laminins widely expressed in mouse bone marrow. However, no laminin alpha1 chain but rather laminin alpha2, alpha4, and alpha5 polypeptides were found in bone marrow. Our data suggest presence of laminin-2 (alpha2beta1gamma1), laminin-8 (alpha4beta1gamma1), and laminin-10 (alpha5beta1gamma1) in bone marrow. Northern blot analysis showed expression of laminin alpha1, alpha2, alpha4, and alpha5 chains in long-term bone marrow cultures, indicating upregulation of laminin alpha1 chain expression in vitro. Laminins containing alpha5 chain, in contrast to laminin-1, were strongly adhesive for multipotent hematopoietic FDCP-mix cells. Integrin alpha6 and beta1 chains mediated this adhesion, as shown by antibody perturbation experiments. Our findings indicate that laminins other than laminin-1 are functional in adhesive interactions in bone marrow.
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| 27. |
- Gustafsson, Renata, et al.
(författare)
-
Expression of the novel gene Ened during mouse and Xenopus embryonic development.
- 2008
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Ingår i: International Journal of Developmental Biology. - : UPV/EHU Press. - 1696-3547 .- 0214-6282. ; 52:8, s. 1119-1122
-
Tidskriftsartikel (refereegranskat)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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| 28. |
- Holmberg, Johan K, et al.
(författare)
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Laminin-211 in skeletal muscle function.
- 2012
-
Ingår i: Cell Adhesion and Migration. - 1933-6918. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- A chain is no stronger than its weakest link is an old idiom that holds true for muscle biology. As the name implies, skeletal muscle's main function is to move the bones. However, for a muscle to transmit force and withstand the stress that contractions give rise to, it relies on a chain of proteins attaching the cytoskeleton of the muscle fiber to the surrounding extracellular matrix. The importance of this attachment is illustrated by a large number of muscular dystrophies caused by interruption of the cytoskeletal-extracellular matrix interaction. One of the major components of the extracellular matrix is laminin, a heterotrimeric glycoprotein and a major constituent of the basement membrane. It has become increasingly apparent that laminins are involved in a multitude of biological functions, including cell adhesion, differentiation, proliferation, migration and survival. This review will focus on the importance of laminin-211 for normal skeletal muscle function.
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| 29. |
- Holmberg, Johan K, et al.
(författare)
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Laminin α2 Chain-Deficiency is Associated with microRNA Deregulation in Skeletal Muscle and Plasma.
- 2014
-
Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 6:Jul 3
-
Tidskriftsartikel (refereegranskat)abstract
- microRNAs (miRNAs) are widespread regulators of gene expression, but little is known of their potential roles in congenital muscular dystrophy type 1A (MDC1A). MDC1A is a severe form of muscular dystrophy caused by mutations in the gene encoding laminin α2 chain. To gain insight into the pathophysiological roles of miRNAs associated with MDC1A pathology, laminin α2 chain-deficient mice were evaluated by quantitative PCR. We demonstrate that expression of muscle-specific miR-1, miR-133a, and miR-206 is deregulated in laminin α2 chain-deficient muscle. Furthermore, expression of miR-223 and miR-21, associated with immune cell infiltration and fibrosis, respectively, is altered. Finally, we show that plasma levels of muscle-specific miRNAs are markedly elevated in laminin α2 chain-deficient mice and partially normalized in response to proteasome inhibition therapy. Altogether, our data suggest important roles for miRNAs in MDC1A pathology and we propose plasma levels of muscle-specific miRNAs as promising biomarkers for the progression of MDC1A.
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| 30. |
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| 31. |
- Häger, Mattias, et al.
(författare)
-
Cib2 binds integrin a7Bb1D and is reduced in laminin a2 chain deficient muscular dystrophy
- 2008
-
Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 283:36, s. 24760-24769
-
Tidskriftsartikel (refereegranskat)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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| 32. |
- Häger, Mattias, et al.
(författare)
-
Intrinsic laryngeal muscles are spared from degeneration in the dy(3k)/dy(3k) mouse model of congenital muscular dystrophy type 1A.
- 2009
-
Ingår i: Muscle and Nerve. - : Wiley. - 0148-639X .- 1097-4598. ; 39:1, s. 91-94
-
Tidskriftsartikel (refereegranskat)abstract
- Deficiency of laminin alpha2 chain leads to a severe form of congenital muscular dystrophy (MDC1A). Here, we analyzed whether the intrinsic laryngeal muscles (ILM) are spared in the dy(3K)/dy(3K) mouse model of complete laminin alpha2 chain absence. No muscle degeneration was evident; expression of various laminin chains was similar to that of limb muscles, and sustained integrin alpha7B expression was noted in laminin alpha2 chain-deficient ILM. We conclude that ILM are spared in MDC1A. Muscle Nerve 39: 91-94, 2009.
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| 33. |
- Häger, Mattias, et al.
(författare)
-
Laminin {alpha}1 Chain Corrects Male Infertility Caused by Absence of Laminin {alpha}2 Chain.
- 2005
-
Ingår i: American Journal of Pathology. - 1525-2191. ; 167:3, s. 823-833
-
Tidskriftsartikel (refereegranskat)abstract
- Laminins are important for basement membrane structure and function. The laminin alpha2 chain is a major component of muscle basement membranes, and mutations in the laminin alpha2 gene lead to congenital muscular dystrophy in humans and mice. Although the laminin alpha2 chain is prominently expressed in testicular basement membranes, its role in testis has remained unclear. Here, we show that laminin alpha1, alpha2, beta1, beta2, gamma 1, and gamma 3 chains are the major laminin chains in basement membranes of seminiferous tubules. In laminin alpha2 chain-deficient dy(3 K)/dy(3 ASK) mice, lack of laminin alpha2 chain led to concurrent reduction of laminin gamma 3 chain and abnormal testicular basement membranes. Seminiferous tubules of laminin alpha2 chain-deficient dy(3 K)/dy(3 K) mice displayed a defect in the timing of lumen formation, resulting in production of fewer spermatides. We also demonstrate that overexpression of laminin alpha1 chain in testis of dy(3 K)/dy(3 K) mice compensated for laminin alpha2 chain deficiency and significantly reversed the appearance of the histopathological features. We thus provide genetic data that laminin alpha chains are essential for normal testicular function in vivo.
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| 34. |
- Kabosova, Andrea, et al.
(författare)
-
Compositional differences between infant and adult human corneal basement membranes
- 2007
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Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783. ; 48:11, s. 4989-4999
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. Adult human corneal epithelial basement membrane ( EBM) and Descemet's membrane ( DM) components exhibit heterogeneous distribution. The purpose of the study was to identify changes of these components during postnatal corneal development. METHODS. Thirty healthy adult corneas and 10 corneas from 12-day- to 3-year-old children were studied by immunofluorescence with antibodies against BM components. RESULTS. Type IV collagen composition of infant corneal central EBM over Bowman's layer changed from alpha 1-alpha 2 to alpha 3-alpha 4 chains after 3 years of life; in the adult, alpha 1-alpha 2 chains were retained only in the limbal BM. Laminin alpha 2 and beta 2 chains were present in the adult limbal BM where epithelial stem cells are located. By 3 years of age, beta 2 chain appeared in the limbal BM. In all corneas, limbal BM contained laminin gamma 3 chain. In the infant DM, type IV collagen alpha 1-alpha 6 chains, perlecan, nidogen-1, nidogen-2, and netrin-4 were found on both faces, but they remained only on the endothelial face of the adult DM. The stromal face of the infant but not the adult DM was positive for tenascin-C, fibrillin-1, SPARC, and laminin-332. Type VIII collagen shifted from the endothelial face of infant DM to its stromal face in the adult. Matrilin-4 largely disappeared after the age of 3 years. CONCLUSIONS. The distribution of laminin gamma 3 chain, nidogen-2, netrin-4, matrilin-2, and matrilin-4 is described in the cornea for the first time. The observed differences between adult and infant corneal BMs may relate to changes in their mechanical strength, corneal cell adhesion and differentiation in the process of postnatal corneal maturation.
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| 35. |
- Klionsky, Daniel J., et al.
(författare)
-
Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
-
Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
-
Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 36. |
- Körner, Zandra, et al.
(författare)
-
Bortezomib Does Not Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy.
- 2016
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Congenital muscular dystrophy with laminin α2 chain-deficiency, also known as MDC1A, is a severe neuromuscular disorder for which there is no cure. Patients with complete laminin α2 chain-deficiency typically have an early onset disease with a more severe muscle phenotype while patients with residual laminin α2 chain expression usually have a milder disease course. Similar genotype-phenotype correlations can be seen in the dy3K/dy3K and dy2J/dy2J mouse models of MDC1A, respectively, with dy3K/dy3K mice presenting the more severe phenotype. Recently, we demonstrated that the proteasome inhibitor bortezomib partially improves muscle morphology and increases lifespan in dy3K/dy3K mice. Here, we explore the use of bortezomib in dy2J/dy2J animals. However, bortezomib neither improved histological hallmarks of disease nor increased muscle strength and locomotive activity in dy2J/dy2J mice. Altogether our data suggest that proteasome inhibition does not mitigate muscle dysfunction caused by partial laminin α2 chain-deficiency. Still, it is possible that proteasome inhibition could be useful as a supportive therapy in patients with complete absence of laminin α2 chain.
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| 37. |
- Körner, Zandra, et al.
(författare)
-
Bortezomib Partially Improves Laminin α2 Chain-Deficient Muscular Dystrophy.
- 2014
-
Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 184:5, s. 1518-1528
-
Tidskriftsartikel (refereegranskat)abstract
- Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin α2 chain), is a severe and incapacitating disease for which no therapy is yet available. We have recently demonstrated that proteasome activity is increased in laminin α2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin α2 chain-deficient dy(3K)/dy(3K) mice. Here, we explore the use of the selective and therapeutic proteasome inhibitor bortezomib (currently used for treatment of relapsed multiple myeloma and mantle cell lymphoma) in dy(3K)/dy(3K) mice and in congenital muscular dystrophy type 1A muscle cells. Outcome measures included quantitative muscle morphology, gene and miRNA expression analyses, proteasome activity, motor activity, and survival. Bortezomib improved several histological hallmarks of disease, partially normalized miRNA expression (miR-1 and miR-133a), and enhanced body weight, locomotion, and survival of dy(3K)/dy(3K) mice. In addition, bortezomib reduced proteasome activity in congenital muscular dystrophy type 1A myoblasts and myotubes. These findings provide evidence that the proteasome inhibitor bortezomib partially reduces laminin α2 chain-deficient muscular dystrophy. Investigation of the clinical efficacy of bortezomib administration in congenital muscular dystrophy type 1A clinical trials may be warranted.
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| 38. |
- Matsumura, Cintia Yuri, et al.
(författare)
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Isobaric Tagging-Based Quantification for Proteomic Analysis: A Comparative Study of Spared and Affected Muscles from mdx Mice at the Early Phase of Dystrophy
- 2013
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:6
-
Tidskriftsartikel (refereegranskat)abstract
- Duchenne muscular dystrophy (DMD) is the most common childhood myopathy, characterized by muscle loss and cardiorespiratory failure. While the genetic basis of DMD is well established, secondary mechanisms associated with dystrophic pathophysiology are not fully clarified yet. In order to obtain new insights into the molecular mechanisms of muscle dystrophy during earlier stages of the disease, we performed a comparative proteomic profile of the spared extraocular muscles (EOM) vs. affected diaphragm from the mdx mice, using a label based shotgun proteomic approach. Out of the 857 identified proteins, 42 to 62 proteins had differential abundance of peptide ions. The calcium-handling proteins sarcalumenin and calsequestrin-1 were increased in control EOM compared with control DIA, reinforcing the view that constitutional properties of EOM are important for their protection against myonecrosis. The finding that galectin-1 (muscle regeneration), annexin A1 (anti-inflammatory) and HSP 47 (fibrosis) were increased in dystrophic diaphragm provides novel insights into the mechanisms through which mdx affected muscles are able to counteract dystrophy, during the early stage of the disease. Overall, the shotgun technique proved to be suitable to perform quantitative comparisons between distinct dystrophic muscles and allowed the suggestion of new potential biomarkers and drug targets for dystrophinopaties.
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| 39. |
- Menezes de Oliveira, Bruno, et al.
(författare)
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Quantitative proteomic analysis reveals metabolic alterations, calcium dysregulation and increased expression of extracellular matrix proteins in laminin α2 chain-deficient muscle.
- 2014
-
Ingår i: Molecular & Cellular Proteomics. - 1535-9484. ; 13:11, s. 3001-3013
-
Tidskriftsartikel (refereegranskat)abstract
- Congenital muscular dystrophy with laminin α2 chain-deficiency (MDC1A) is one of the most severe forms of muscular disease and is characterized by severe muscle weakness and delayed motor milestones. The genetic basis of MDC1A is well-known, yet the secondary mechanisms ultimately leading to muscle degeneration and subsequent connective tissue infiltration are not fully understood. In order to obtain new insights into the molecular mechanisms underlying MDC1A, we performed a comparative proteomic analysis of affected muscles (diaphragm and gastrocnemius) from laminin α2 chain-deficient dy3K/dy3K mice, using the multidimensional protein identification technology combined with tandem mass tags. Out of the around 700 identified proteins, 113 and 101 proteins, respectively, were differentially expressed in the diseased gastrocnemius and diaphragm muscles compared to normal muscles. A large portion of these proteins are involved in different metabolic processes, bind calcium or are expressed in the extracellular matrix. Our findings suggest that metabolic alterations and calcium dysregulation could be novel mechanisms that underlie MDC1A and might be targets that should be explored for therapy. Also, detailed knowledge of the composition of fibrotic tissue, rich in extracellular matrix proteins, in laminin α2 chain deficient muscle may help to design future anti-fibrotic treatment. All MS data have been deposited in the ProteomeXchange with identifier PXD000978 (http://proteomecentral.proteomexchange.org/dataset/PXD000978).
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| 40. |
- Nyström, Alexander, et al.
(författare)
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Extraocular muscle is spared upon complete laminin alpha2 chain deficiency : comparative expression of laminin and integrin isoforms.
- 2006
-
Ingår i: Matrix Biology. - : Elsevier. - 0945-053X .- 1569-1802. ; 25:6, s. 382-385
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the gene encoding laminin (LM) alpha2 chain cause congenital muscular dystrophy. Here, we show that extraocular muscle (EOM) is spared upon complete LMalpha2 chain absence. The major LM chains in limb muscle basement membranes are alpha2, beta1, beta2 and gamma1 whereas alpha2, alpha4, beta1, beta2 and gamma1 chains are expressed in EOM. Expression of LMalpha4 chain mRNA is further increased in LMalpha2 chain deficient EOM. Mainly integrin alpha7X1 subunit, which binds to laminin-411, is expressed in EOM and in contrast to dystrophic limb muscle, sustained integrin alpha7B expression is seen in LMalpha2 chain deficient EOM. We propose that LMalpha4 chain, possibly by binding to integrin alpha7BX1beta1D, protects EOM in LMalpha2 chain deficient muscular dystrophy.
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| 41. |
- Oblander, S A, et al.
(författare)
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Distinctive functions of membrane type 1 matrix-metalloprotease (MT1-MMP or MMP-14) in lung and submandibular gland development are independent of its role in pro-MMP-2 activation
- 2005
-
Ingår i: Developmental Biology. - : Elsevier BV. - 1095-564X .- 0012-1606. ; 277:1, s. 255-269
-
Tidskriftsartikel (refereegranskat)abstract
- Membrane type 1-matrix metalloprotease (MT1-MMP or MMP-14) is a major activator of pro-MMP-2 and is essential for skeletal development. We show here that it is required for branching morphogenesis of the submandibular gland but not the lung. Instead, in the lung, it is essential for postnatal development of alveolar septae. Lung development in Mmp14-/- mice is arrested at the prealveolar stage with compensatory hyperinflation of immature saccules. Mmp2-/- mice lacked comparable defects in the lung and submandibular gland, suggesting that NIT1-MMP acts via mechanisms independent of pro-MMP-2 activation. Since the developmental defects in the lung are first manifest around the time of initial vascularization (E16.5), we investigated the behavior of pulmonary endothelial cells from Mmp14+/+ and Mmp14-/- mice. Endothelial cells from lungs of 1-week-old Mmp14-/- mice show reduced migration and formation of three-dimensional structures on Matrigel. Since pulmonary septal development requires capillary growth, the underlying mechanism of pulmonary hypoplasia in Mmp14-/- mice may be defective angiogenesis, supporting a model in which angiogenesis is a critical rate-limiting step for acquisition of pulmonary parenchymal mass.
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| 42. |
- Rauch, Uwe, et al.
(författare)
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Increased Neointimal Thickening in Dystrophin-Deficient mdx Mice.
- 2012
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The dystrophin gene, which is mutated in Duchenne muscular dystrophy (DMD), encodes a large cytoskeletal protein present in muscle fibers. While dystrophin in skeletal muscle has been extensively studied, the function of dystrophin in vascular smooth muscle is less clear. Here, we have analyzed the role of dystrophin in injury-induced arterial neointima formation. METHODOLOGY/PRINCIPAL FINDINGS: We detected a down-regulation of dystrophin, dystroglycan and β-sarcoglycan mRNA expression when vascular smooth muscle cells de-differentiate in vitro. To further mimic development of intimal lesions, we performed a collar-induced injury of the carotid artery in the mdx mouse, a model for DMD. As compared with control mice, mdx mice develop larger lesions with increased numbers of proliferating cells. In vitro experiments demonstrate increased migration of vascular smooth muscle cells from mdx mice whereas the rate of proliferation was similar in cells isolated from wild-type and mdx mice. CONCLUSIONS/SIGNIFICANCE: These results show that dystrophin deficiency stimulates neointima formation and suggest that expression of dystrophin in vascular smooth muscle cells may protect the artery wall against injury-induced intimal thickening.
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| 43. |
- Rauch, Uwe, et al.
(författare)
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Laminin isoforms in atherosclerotic arteries from mice and man.
- 2011
-
Ingår i: Histology and Histopathology. - 1699-5848. ; 26:6, s. 711-724
-
Tidskriftsartikel (refereegranskat)abstract
- The properties of the arterial vasculature depend to a large extent on the activities of smooth muscle cells, which, in turn, are determined by their extracellular environment. During pathological conditions, such as atherosclerosis, this interaction is altered. In close proximity to medial smooth muscle cells are basement membrane components, such as different isoforms of laminin. These proteins can have great impact on cellular function via interaction with cell surface integrins. However, knowledge of laminins in smooth muscle cell basement membranes during normal and pathological conditions is scarce. Therefore, we have analyzed the presence of laminin isoforms in atherosclerotic lesions of apolipoprotein E (ApoE)-deficient mice. Our study revealed that the laminin chain isotype composition within atherosclerotic plaque tissue was different from the chain composition in the media. In addition, obvious differences in laminin chain composition could be observed in areas of the media, which were or were not associated with plaque tissue. Our major findings demonstrate that laminin gamma3 was exclusively present in media associated with plaque tissue. Laminin alpha2 was also enriched in these medial areas. Plaque tissue was predominantly enriched in laminin alpha5 chains. This general distribution applied to lesions both with and without a fibrous cap-like structure. The differential distribution of laminin chains were partially accompanied by changes in the presence of the integrin alpha subunits 7 and V. The distribution of laminin chains in human atherosclerotic arteries, with different size and morphology, grossly resembled their distribution in mouse arteries.
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| 44. |
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| 45. |
- Schéele, Susanne, et al.
(författare)
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Laminin isoforms in development and disease.
- 2007
-
Ingår i: Journal of Molecular Medicine. - : Springer Science and Business Media LLC. - 1432-1440 .- 0946-2716. ; 85:8, s. 825-836
-
Forskningsöversikt (refereegranskat)abstract
- The members of the laminin family of heterotrimers are major constituents of all basement membranes, sheet-like extracellular structures, present in almost all organs. The laminins bind to cell surface receptors and thereby tightly connect the basement membrane to the adjacent cell layer. This provides for the specific basement membrane functions to stabilize cellular structures, to serve as effective physical barriers, and furthermore, to govern cell fate by inducing intracellular signalling cascades. Many different types of diseases involve basement membranes and laminins. Metastasizing solid tumors must pass through basement membranes to reach the vascular system, and various microbes and viruses enter the cells through direct interaction with laminins. Furthermore, whereas mutations in one specific laminin chain lead to a muscular disorder, mutations of other laminin chains cause skin blistering and kidney defects, respectively. This review summarizes recent progress concerning the molecular mechanisms of laminins in development and disease. The current knowledge may lead to clinical treatment of lamininopathies and may include stem-cell approaches as well as gene therapy.
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| 46. |
- Schéele, Susanne, et al.
(författare)
-
Monoclonal anti-mouse laminin antibodies: AL-1 reacts with laminin alpha1 chain, AL-2 with laminin beta1 chain, and AL-4 with the coiled-coil domain of laminin beta1 chain.
- 2006
-
Ingår i: Matrix Biology. - : Elsevier BV. - 1569-1802 .- 0945-053X. ; 25:5, s. 301-305
-
Tidskriftsartikel (refereegranskat)abstract
- We analyzed the reactivity of three different commercially available rat monoclonal antibodies raised against mouse laminin-a1 beta 1 gamma 1 (laminin-11), AL-1, AL-2, and AL-4. Using ELISA assays, Western blot analysis and inummostainings we present refined epitope maps for these three laminin monoclonals. AL-1 reacted, as predicted with laminin alpha 1 chain. AL-4 has also been marketed as an alpha 1 chain specific probe, but we show here that AL-4 detects mouse laminin beta 1 chain, in the distal part of the coiled-coil region. AL-2 was predicted to react with all three chains near the cross-region, but seems to primarily react with laminin beta 1 chain. (c) 2006 Elsevier B.V./Intemational Society of Matrix Biology. All rights reserved.
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| 47. |
- Sciandra, Francesca, et al.
(författare)
-
Dystroglycan: a possible mediator for reducing congenital muscular dystrophy?
- 2007
-
Ingår i: Trends in Biotechnology. - : Elsevier BV. - 0167-7799. ; 25:6, s. 262-268
-
Forskningsöversikt (refereegranskat)abstract
- alpha-Dystroglycan is a highly glycosylated peripheral protein forming a complex with the membrane-spanning beta-dystroglycan and establishing a connection between the extracellular matrix and the cytoskeleton. In skeletal muscle, as part of the larger dystrophin-glycoprotein complex, dystroglycan is believed to be essential for maintaining the structural and functional stability of muscle fibers. Recent work highlights the role of abnormal dystroglycan glycosylation at the basis of glycosyltransferase-deficient congenital muscular dystrophies. Notably, modulation of glycosyltransferase activity can restore alpha-dystroglycan receptor function in these disorders. Moreover, transgenic approaches favoring the interaction between dystroglycan and the extracellular matrix molecules also represent an innovative way to restore skeletal muscle structure. These pioneering approaches might comprise an important first step towards the design of gene-transfer-based strategies for the rescue of congenital muscular dystrophies involving dystroglycan.
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| 48. |
- Shami, Annelie, et al.
(författare)
-
Dystrophin deficiency reduces atherosclerotic plaque development in ApoE-null mice.
- 2015
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- Dystrophin of the dystrophin-glycoprotein complex connects the actin cytoskeleton to basement membranes and loss of dystrophin results in Duchenne muscular dystrophy. We have previously shown injury-induced neointima formation of the carotid artery in mice with the mdx mutation (causing dystrophin deficiency) to be increased. To investigate the role of dystrophin in intimal recruitment of smooth muscle cells (SMCs) that maintains plaque stability in atherosclerosis we applied a shear stress-modifying cast around the carotid artery of apolipoprotein E (ApoE)-null mice with and without the mdx mutation. The cast induces formation of atherosclerotic plaques of inflammatory and SMC-rich/fibrous phenotypes in regions of low and oscillatory shear stress, respectively. Unexpectedly, presence of the mdx mutation markedly reduced the development of the inflammatory low shear stress plaques. Further characterization of the low shear stress plaques in ApoE-null mdx mice demonstrated reduced infiltration of CD3(+) T cells, less laminin and a higher SMC content. ApoE-null mdx mice were also found to have a reduced fraction of CD3(+) T cells in the spleen and lower levels of cytokines and monocytes in the circulation. The present study is the first to demonstrate a role for dystrophin in atherosclerosis and unexpectedly shows that this primarily involves immune cells.
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| 49. |
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| 50. |
- Åkerlund, Mikael, et al.
(författare)
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Laminin alpha1 domains LG4-5 are essential for the complete differentiation of visceral endoderm.
- 2009
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Ingår i: Cell and Tissue Research. - : Springer Science and Business Media LLC. - 1432-0878 .- 0302-766X. ; 338:1, s. 129-137
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Tidskriftsartikel (refereegranskat)abstract
- The heterotrimeric basement membrane protein laminin-111 is essential for early mouse embryogenesis. Its beta1 and gamma1 chains are crucial for endoderm differentiation and for the formation of basement membranes, whereas alpha1 chain null mice only lack the extraembryonic Reichert's membrane. Nevertheless, mice deficient in the cell-binding alpha1 globular domains 4-5 (LG4-5) have a more severe phenotype than animals devoid of the whole alpha1 chain, as these domains are required for the formation of a polarized ectoderm. However, the influence of the alpha1LG4-5 domains on endoderm differentiation is unclear. We have used microarray analysis to compare the expression profiles of normal and alpha1LG4-5-deficient embryoid bodies and show that genes encoding secreted plasma proteins and proteins involved in endocytosis are reduced in alpha1LG4-5-deficient embryoid bodies, indicating incomplete differentiation of the visceral endoderm. Moreover, mice lacking alpha1LG4-5 display endoderm disorganization and a defective expression of the endoderm marker Dab2. We hypothesize that alpha1LG4-5 domains provide an autocrine signal necessary for the complete differentiation of a functional visceral endoderm and vital signals for the polarization of the epiblast.
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