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Sarah J Smith, Jeffrey C Wang, Vandana A Gupta, James J Dowling
Merosin deficient congenital muscular dystrophy (MDC1A) is a severe neuromuscular disorder with onset in infancy that is associated with severe morbidities (particularly wheelchair dependence) and early mortality. It is caused by recessive mutations in the LAMA2 gene that encodes a subunit of the extracellular matrix protein laminin 211. At present, there are no treatments for this disabling disease. The zebrafish has emerged as a powerful model system for the identification of novel therapies. However, drug discovery in the zebrafish is largely dependent on the identification of phenotypes suitable for chemical screening...
2017: PloS One
Karen K McKee, Stephanie C Crosson, Sarina Meinen, Judith R Reinhard, Markus A Rüegg, Peter D Yurchenco
Mutations in laminin α2-subunit (Lmα2, encoded by LAMA2) are linked to approximately 30% of congenital muscular dystrophy cases. Mice with a homozygous mutation in Lama2 (dy2J mice) express a nonpolymerizing form of laminin-211 (Lm211) and are a model for ambulatory-type Lmα2-deficient muscular dystrophy. Here, we developed transgenic dy2J mice with muscle-specific expression of αLNNd, a laminin/nidogen chimeric protein that provides a missing polymerization domain. Muscle-specific expression of αLNNd in dy2J mice resulted in strong amelioration of the dystrophic phenotype, manifested by the prevention of fibrosis and restoration of forelimb grip strength...
March 1, 2017: Journal of Clinical Investigation
Christopher M Penton, Vasudeo Badarinarayana, Joy Prisco, Elaine Powers, Mark Pincus, Ronald E Allen, Paul R August
BACKGROUND: Large-scale expansion of myogenic progenitors is necessary to support the development of high-throughput cellular assays in vitro and to advance genetic engineering approaches necessary to develop cellular therapies for rare muscle diseases. However, optimization has not been performed in order to maintain the differentiation capacity of myogenic cells undergoing long-term cell culture. Multiple extracellular matrices have been utilized for myogenic cell studies, but it remains unclear how different matrices influence long-term myogenic activity in culture...
December 13, 2016: Skeletal Muscle
Sabrina D Clark, Mary B Nabity, Rachel E Cianciolo, Brianna Dufek, Dominic Cosgrove
BACKGROUND: X-linked Alport syndrome (XLAS), caused by mutations in the type IV collagen COL4A5 gene, accounts for approximately 80% of human Alport syndrome. Dogs with XLAS have a similar clinical progression. Prior studies in autosomal recessive Alport mice demonstrated early mesangial cell invasion as the source of laminin 211 in the glomerular basement membrane (GBM), leading to proinflammatory signaling. The objective of this study was to verify this process in XLAS dogs. METHODS: XLAS dogs and WT littermates were monitored with serial clinicopathologic data and kidney biopsies...
2016: PloS One
Paulomi Mehta, Xianhua Piao
Adhesion G protein-coupled receptors (aGPCRs) are a large family of transmembrane proteins that play important roles in many processes during development, primarily through cell-cell and cell-extracellular matrix (ECM) interactions. In the nervous system, they have been linked to the complex process of myelination, both in the central and peripheral nervous system. GPR126 is essential in Schwann cell-mediated myelination in the peripheral nervous system (PNS), while GPR56 is involved in oligodendrocyte development central nervous system (CNS) myelination...
April 2017: Developmental Dynamics: An Official Publication of the American Association of Anatomists
Heather L Glasgow, Michael A Whitney, Larry A Gross, Beth Friedman, Stephen R Adams, Jessica L Crisp, Timon Hussain, Andreas P Frei, Karel Novy, Bernd Wollscheid, Quyen T Nguyen, Roger Y Tsien
Target-blind activity-based screening of molecular libraries is often used to develop first-generation compounds, but subsequent target identification is rate-limiting to developing improved agents with higher specific affinity and lower off-target binding. A fluorescently labeled nerve-binding peptide, NP41, selected by phage display, highlights peripheral nerves in vivo. Nerve highlighting has the potential to improve surgical outcomes by facilitating intraoperative nerve identification, reducing accidental nerve transection, and facilitating repair of damaged nerves...
October 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
Ayako Uchinaka, Kanako Tasaka, Yoko Mizuno, Yoshitaka Maeno, Tsuyoshi Ban, Seiji Mori, Yoshinosuke Hamada, Shigeru Miyagawa, Atsuhiro Saito, Yoshiki Sawa, Nariaki Matsuura, Kohzo Nagata, Hirofumi Yamamoto, Naomasa Kawaguchi
OBJECTIVES: Skeletal myoblast sheet (SMB) transplantation, a method used for treating failing hearts, results in the secretion of cytokines that improve heart function. Enhancing the survival rate of implanted myoblasts should yield more continuous and effective therapies. We hypothesized that laminin-211 (merosin), a major component of skeletal muscle extracellular matrix (ECM), which mediates cell-to-ECM adhesion by binding to α-dystroglycan (αDG) on muscle cells, could inhibit detachment of implanted myoblasts from host myocardia...
September 23, 2016: European Journal of Cardio-thoracic Surgery
Anja Fleger-Weckmann, Yasemin Üstün, Jennifer Kloepper, Ralf Paus, Wilhelm Bloch, Zu-Lin Chen, Jeannine Wegner, Lydia Sorokin, Lutz Langbein, Beate Eckes, Paola Zigrino, Thomas Krieg, Roswitha Nischt
Laminins are the most abundant non-collagenous basement membrane (BM) components, composed of an α, β and γ chain. The laminin γ1 chain, encoded by LAMC1, is the most abundant γ chain. The main laminin isoforms in the dermo-epidermal junction (DEJ) are laminin-332, laminin-511 and laminin-211, the latter being restricted to the lower part of hair follicles (HFs). Complete deletion of LAMC1 results in lethality around embryonic day 5.5. To study the function of laminin γ1 containing isoforms in skin development and maturation after birth, we generated mice lacking LAMC1 expression in basal keratinocytes (LAMC1(EKO)) using the keratin 14 (K14) Cre/loxP system...
December 2016: Matrix Biology: Journal of the International Society for Matrix Biology
Brianna Dufek, Daniel T Meehan, Duane Delimont, Linda Cheung, Michael Anne Gratton, Grady Phillips, Wenping Song, Shiguang Liu, Dominic Cosgrove
Recent work demonstrates that Alport glomerular disease is mediated through a biomechanical strain-sensitive activation of mesangial actin dynamics. This occurs through a Rac1/CDC42 cross-talk mechanism that results in the invasion of the subcapillary spaces by mesangial filopodia. The filopodia deposit mesangial matrix proteins in the glomerular basement membrane, including laminin 211, which activates focal adhesion kinase in podocytes culminating in the up-regulation of proinflammatory cytokines and metalloproteinases...
August 2016: Kidney International
Madeleine Durbeej
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...
2015: Current Topics in Membranes
Kinga I Gawlik, Madeleine Durbeej
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...
2015: Scientific Reports
Teuta Domi, Emanuela Porrello, Daniele Velardo, Alessia Capotondo, Alessandra Biffi, Rossana Tonlorenzi, Stefano Amadio, Alessandro Ambrosi, Yuko Miyagoe-Suzuki, Shin'ichi Takeda, Markus A Ruegg, Stefano Carlo Previtali
BACKGROUND: Merosin-deficient congenital muscular dystrophy type-1A (MDC1A) is characterized by progressive muscular dystrophy and dysmyelinating neuropathy caused by mutations of the α2 chain of laminin-211, the predominant laminin isoform of muscles and nerves. MDC1A has no available treatment so far, although preclinical studies showed amelioration of the disease by the overexpression of miniagrin (MAG). MAG reconnects orphan laminin-211 receptors to other laminin isoforms available in the extracellular matrix of MDC1A mice...
2015: Skeletal Muscle
Cindy V Leiton, Azeez Aranmolate, Christopher Eyermann, Michael J Menezes, Luisa F Escobar-Hoyos, Solomon Husain, Steve J Winder, Holly Colognato
The cell surface receptor dystroglycan mediates interactions between oligodendroglia and laminin-211, an extracellular matrix protein that regulates timely oligodendroglial development. However, dystroglycan's precise role in oligodendroglial development and the potential mechanisms to regulate laminin-dystroglycan interactions remain unknown. Here we report that oligodendroglial dystroglycan is cleaved by metalloproteinases, thereby uncoupling oligodendroglia from laminin binding. Dystroglycan cleavage is selectively stimulated by oligodendrocyte progenitor cell attachment to laminin-211, but not laminin-111 or poly-D-lysine...
November 2015: Journal of Neurochemistry
Sarah C Petersen, Rong Luo, Ines Liebscher, Stefanie Giera, Sung-Jin Jeong, Amit Mogha, Monica Ghidinelli, M Laura Feltri, Torsten Schöneberg, Xianhua Piao, Kelly R Monk
Myelin ensheathes axons to allow rapid propagation of action potentials and proper nervous system function. In the peripheral nervous system, Schwann cells (SCs) radially sort axons into a 1:1 relationship before wrapping an axonal segment to form myelin. SC myelination requires the adhesion G protein-coupled receptor GPR126, which undergoes autoproteolytic cleavage into an N-terminal fragment (NTF) and a seven-transmembrane-containing C-terminal fragment (CTF). Here we show that GPR126 has domain-specific functions in SC development whereby the NTF is necessary and sufficient for axon sorting, whereas the CTF promotes wrapping through cAMP elevation...
February 18, 2015: Neuron
Michael J Menezes, Freyja K McClenahan, Cindy V Leiton, Azeez Aranmolate, Xiwei Shan, Holly Colognato
Laminins are major constituents of the gliovascular basal lamina of the blood-brain barrier (BBB); however, the role of laminins in BBB development remains unclear. Here we report that Lama2(-/-) mice, lacking expression of the laminin α2 subunit of the laminin-211 heterotrimer expressed by astrocytes and pericytes, have a defective BBB in which systemically circulated tracer leaks into the brain parenchyma. The Lama2(-/-) vascular endothelium had significant abnormalities, including altered integrity and composition of the endothelial basal lamina, inappropriate expression of embryonic vascular endothelial protein MECA32, substantially reduced pericyte coverage, and tight junction abnormalities...
November 12, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Liang Ning, Hidetake Kurihara, Susana de Vega, Naoki Ichikawa-Tomikawa, Zhuo Xu, Risa Nonaka, Saiko Kazuno, Yoshihiko Yamada, Jeffrey H Miner, Eri Arikawa-Hirasawa
Laminin α1 (LAMA1), a subunit of the laminin-111 basement membrane component, has been implicated in various biological functions in vivo and in vitro. Although LAMA1 is present in kidney, its roles in the kidney are unknown because of early embryonic lethality. Herein, we used a viable conditional knockout mouse model with a deletion of Lama1 in the epiblast lineage (Lama1(CKO)) to study the role of LAMA1 in kidney development and function. Adult Lama1(CKO) mice developed focal glomerulosclerosis and proteinuria with age...
June 2014: American Journal of Pathology
Katherine G Meilleur, Kristen Zukosky, Livija Medne, Pierre Fequiere, Nina Powell-Hamilton, Thomas L Winder, Abdulaziz Alsaman, Ayman W El-Hattab, Jahannaz Dastgir, Ying Hu, Sandra Donkervoort, Jeffrey A Golden, Ralph Eagle, Richard Finkel, Mena Scavina, Ian C Hood, Lucy B Rorke-Adams, Carsten G Bönnemann
Dystroglycanopathies are a subtype of congenital muscular dystrophy of varying severity that can affect the brain and eyes, ranging from Walker-Warburg syndrome with severe brain malformation to milder congenital muscular dystrophy presentations with affected or normal cognition and later onset. Mutations in dystroglycanopathy genes affect a specific glycoepitope on α-dystroglycan; of the 14 genes implicated to date, LARGE encodes the glycosyltransferase that adds the final xylose and glucuronic acid, allowing α-dystroglycan to bind ligands, including laminin 211 and neurexin...
May 2014: Journal of Neuropathology and Experimental Neurology
Marta Pellegatta, Adèle De Arcangelis, Alessandra D'Urso, Alessandro Nodari, Desirée Zambroni, Monica Ghidinelli, Vittoria Matafora, Courtney Williamson, Elisabeth Georges-Labouesse, Jordan Kreidberg, Ulrike Mayer, Karen K McKee, Peter D Yurchenco, Angelo Quattrini, Lawrence Wrabetz, Maria Laura Feltri
During development, Schwann cells extend lamellipodia-like processes to segregate large- and small-caliber axons during the process of radial sorting. Radial sorting is a prerequisite for myelination and is arrested in human neuropathies because of laminin deficiency. Experiments in mice using targeted mutagenesis have confirmed that laminins 211, 411, and receptors containing the β1 integrin subunit are required for radial sorting; however, which of the 11 α integrins that can pair with β1 forms the functional receptor is unknown...
November 13, 2013: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Pam M Van Ry, Priscilla Minogue, Bradley L Hodges, Dean J Burkin
Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a severe and fatal muscle-wasting disease with no cure. MDC1A patients and the dy(W-/-) mouse model exhibit severe muscle weakness, demyelinating neuropathy, failed muscle regeneration and premature death. We have recently shown that laminin-111, a form of laminin found in embryonic skeletal muscle, can substitute for the loss of laminin-211/221 and prevent muscle disease progression in the dy(W-/-) mouse model. What is unclear from these studies is whether laminin-111 can restore failed regeneration to laminin-α2-deficient muscle...
January 15, 2014: Human Molecular Genetics
Marisa Zallocchi, Brianna M Johnson, Daniel T Meehan, Duane Delimont, Dominic Cosgrove
Alport syndrome, hereditary glomerulonephritis with hearing loss, results from mutations in type IV collagen COL4A3, COL4A4, or COL4A5 genes. The mechanism for delayed glomerular disease onset is unknown. Comparative analysis of Alport mice and CD151 knockout mice revealed progressive accumulation of laminin 211 in the glomerular basement membrane. We show mesangial processes invading the capillary loops of both models as well as in human Alport glomeruli, as the likely source of this laminin. L-NAME salt-induced hypertension accelerated mesangial cell process invasion...
October 2013: American Journal of Pathology
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