173 results match your criteria form agrin

Conservation and Innovation: Versatile Roles for LRP4 in Nervous System Development.

J Dev Biol 2021 Mar 14;9(1). Epub 2021 Mar 14.

Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA.

As the nervous system develops, connections between neurons must form to enable efficient communication. This complex process of synaptic development requires the coordination of a series of intricate mechanisms between partner neurons to ensure pre- and postsynaptic differentiation. Many of these mechanisms employ transsynaptic signaling via essential secreted factors and cell surface receptors to promote each step of synaptic development. Read More

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POMK regulates dystroglycan function via LARGE1-mediated elongation of matriglycan.

Elife 2020 09 25;9. Epub 2020 Sep 25.

Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, United States.

Matriglycan [-GlcA-β1,3-Xyl-α1,3-] serves as a scaffold in many tissues for extracellular matrix proteins containing laminin-G domains including laminin, agrin, and perlecan. Like-acetyl-glucosaminyltransferase 1 (LARGE1) synthesizes and extends matriglycan on α-dystroglycan (α-DG) during skeletal muscle differentiation and regeneration; however, the mechanisms which regulate matriglycan elongation are unknown. Here, we show that Protein -Mannose Kinase (POMK), which phosphorylates mannose of core M3 (GalNAc-β1,3-GlcNAc-β1,4-Man) preceding matriglycan synthesis, is required for LARGE1-mediated generation of full-length matriglycan on α-DG (~150 kDa). Read More

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September 2020

Possible implications of dysregulated nicotinic acetylcholine receptor diffusion and nanocluster formation in myasthenia gravis.

Neural Regen Res 2021 Feb;16(2):242-246

Biomedical Research Institute (BIOMED) UCA-CONICET, Buenos Aires, Argentina.

Myasthenia gravis is a rare and invalidating disease affecting the neuromuscular junction of voluntary muscles. The classical form of this autoimmune disease is characterized by the presence of antibodies against the most abundant protein in the neuromuscular junction, the nicotinic acetylcholine receptor. Other variants of the disease involve autoimmune attack of non-receptor scaffolding proteins or enzymes essential for building or maintaining the integrity of this peripheral synapse. Read More

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February 2021

Myasthenia Gravis: From the Viewpoint of Pathogenicity Focusing on Acetylcholine Receptor Clustering, Trans-Synaptic Homeostasis and Synaptic Stability.

Front Mol Neurosci 2020 28;13:86. Epub 2020 May 28.

Neurological Center, Kanazawa-Nishi Hospital, Kanazawa, Japan.

Myasthenia gravis (MG) is a disease of the postsynaptic neuromuscular junction (NMJ) where nicotinic acetylcholine (ACh) receptors (AChRs) are targeted by autoantibodies. Search for other pathogenic antigens has detected the antibodies against muscle-specific tyrosine kinase (MuSK) and low-density lipoprotein-related protein 4 (Lrp4), both causing pre- and post-synaptic impairments. Agrin is also suspected as a fourth pathogen. Read More

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An improved method for culturing myotubes on laminins for the robust clustering of postsynaptic machinery.

Sci Rep 2020 03 11;10(1):4524. Epub 2020 Mar 11.

Laboratory of Synaptogenesis, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.

Motor neurons form specialized synapses with skeletal muscle fibers, called neuromuscular junctions (NMJs). Cultured myotubes are used as a simplified in vitro system to study the postsynaptic specialization of muscles. The stimulation of myotubes with the glycoprotein agrin or laminin-111 induces the clustering of postsynaptic machinery that contains acetylcholine receptors (AChRs). Read More

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A new protein curbs the hypertrophic effect of myostatin inhibition, adding remarkable endurance to motor performance in mice.

PLoS One 2020 11;15(3):e0228653. Epub 2020 Mar 11.

Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy.

Current efforts to improve muscle performance are focused on muscle trophism via inhibition of the myostatin pathway: however they have been unsuccessful in the clinic to date. In this study, a novel protein has been created by combining the soluble activin receptor, a strong myostatin inhibitor, to the C-terminal agrin nLG3 domain (ActR-Fc-nLG3) involved in the development and maintenance of neuromuscular junctions. Both domains are connected via the constant region of an Igg1 monoclonal antibody. Read More

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1α, 25(OH)D regulates agrin-induced acetylcholine receptor clustering through upregulation of rapsyn expression in C2C12 myotubes.

Biochem Biophys Res Commun 2020 Feb 18. Epub 2020 Feb 18.

Laboratory of Muscle Biology, Tokyo Woman's Christian University, 2-6-1 Zempukuji, Suginami-ku, Tokyo, 167-8585, Japan. Electronic address:

The active form of vitamin D (1α, 25-dihydroxyvitamin D [1α, 25(OH)D], referred to as 1,25D) has been suggested to play a pivotal role in skeletal muscle function and metabolism. However, the mechanisms through which 1,25D functions in this tissue remain to be elucidated. Recent studies have shown that vitamin D signaling regulates neuromuscular maintenance and improves locomotion in mice. Read More

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February 2020

MMP-mediated modulation of ECM environment during axonal growth and NMJ development.

Neurosci Lett 2020 04 12;724:134822. Epub 2020 Feb 12.

School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. Electronic address:

Motor neurons, skeletal muscles, and perisynaptic Schwann cells interact with extracellular matrix (ECM) to form the tetrapartite synapse in the peripheral nervous system. Dynamic remodeling of ECM composition is essential to diversify its functions for distinct cellular processes during neuromuscular junction (NMJ) development. In this review, we give an overview of the proteolytic regulation of ECM proteins, particularly by secreted and membrane-type matrix metalloproteinases (MMPs), in axonal growth and NMJ development. Read More

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SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody.

Neurol Neuroimmunol Neuroinflamm 2020 01 12;7(1). Epub 2019 Dec 12.

From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic University, Rome, Italy.

Objective: To determine whether an SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitor would increase muscle-specific kinase (MuSK) phosphorylation and override the inhibitory effect of MuSK-antibodies (Abs).

Methods: The effect of the SHP2 inhibitor NSC-87877 on MuSK phosphorylation and AChR clustering was tested in C2C12 myotubes with 31 MuSK-myasthenia gravis (MG) sera and purified MuSK-MG IgG4 preparations.

Results: In the absence of MuSK-MG Abs, NSC-87877 increased MuSK phosphorylation and the number of AChR clusters in C2C12 myotubes in vitro and in DOK7-overexpressing C2C12 myotubes that form spontaneous AChR clusters. Read More

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January 2020

Nerve, Muscle, and Synaptogenesis.

Cells 2019 11 16;8(11). Epub 2019 Nov 16.

Christie Street, Suite 914, Toronto, ON M6G 3E3, Canada.

The vertebrate skeletal neuromuscular junction (NMJ) has long served as a model system for studying synapse structure, function, and development. Over the last several decades, a neuron-specific isoform of agrin, a heparan sulfate proteoglycan, has been identified as playing a central role in synapse formation at all vertebrate skeletal neuromuscular synapses. While agrin was initially postulated to be the inductive molecule that initiates synaptogenesis, this model has been modified in response to work showing that postsynaptic differentiation can develop in the absence of innervation, and that synapses can form in transgenic mice in which the agrin gene is ablated. Read More

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November 2019

Agrin-Lrp4-Ror2 signaling regulates adult hippocampal neurogenesis in mice.

Elife 2019 07 3;8. Epub 2019 Jul 3.

Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, United States.

Adult neurogenesis in the hippocampus may represent a form of plasticity in brain functions including mood, learning and memory. However, mechanisms underlying neural stem/progenitor cells (NSPCs) proliferation are not well understood. We found that Agrin, a factor critical for neuromuscular junction formation, is elevated in the hippocampus of mice that are stimulated by enriched environment (EE). Read More

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Identification of Candidate Protein Markers in Skeletal Muscle of Laminin-211-Deficient CMD Type 1A-Patients.

Front Neurol 2019 7;10:470. Epub 2019 May 7.

Department of Pediatric Neurology, Developmental Neurology and Social Pediatrics, University of Duisburg-Essen, Essen, Germany.

Laminin-211 deficiency leads to the most common form of congenital muscular dystrophy in childhood, MDC1A. The clinical picture is characterized by severe muscle weakness, brain abnormalities and delayed motor milestones defining MDC1A as one of the most severe forms of congenital muscular diseases. Although the molecular genetic basis of this neurological disease is well-known and molecular studies of mouse muscle and human cultured muscle cells allowed first insights into the underlying pathophysiology, the definition of marker proteins in human vulnerable tissue such as skeletal muscle is still lacking. Read More

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Amelioration of Muscle and Nerve Pathology in LAMA2 Muscular Dystrophy by AAV9-Mini-Agrin.

Mol Ther Methods Clin Dev 2018 Jun 31;9:47-56. Epub 2018 Jan 31.

Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

LAMA2-related muscular dystrophy (LAMA2 MD) is the most common and fatal form of early-onset congenital muscular dystrophies. Due to the large size of the laminin α2 cDNA and heterotrimeric structure of the protein, it is challenging to develop a gene-replacement therapy. Our group has developed a novel adeno-associated viral (AAV) vector carrying the mini-agrin, which is a non-homologous functional substitute for the mutated laminin α2. Read More

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Muscle-Specific Tyrosine Kinase and Myasthenia Gravis Owing to Other Antibodies.

Neurol Clin 2018 05;36(2):293-310

Department of Neuroscience and Regenerative Medicine, Augusta University, 1120 15th Street, CA-2014, Augusta, GA 30912, USA.

Around 20% of patients with myasthenia gravis are acetylcholine receptor antibody negative; muscle-specific tyrosine kinase antibodies (MuSK) were identified as the cause of myasthenia gravis in 30% to 40% of these cases. Anti MuSK myasthenia gravis is associated with specific clinical phenotypes. One is a bulbar form with fewer ocular symptoms. Read More

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Practical Anatomy of the Neuromuscular Junction in Health and Disease.

Neurol Clin 2018 05;36(2):231-240

Research Team for Geriatric Medicine, Tokyo Metropolitan Institute of Gerontology, Sakae-cho 35-2, Itabashi-ku, Tokyo 173-0015, Japan.

Neuromuscular junctions (NMJs) form between nerve terminals of spinal cord motor neurons and skeletal muscles, and perisynaptic Schwann cells and kranocytes cap NMJs. One muscle fiber has one NMJ, which is innervated by one motor nerve terminal. NMJs are excitatory synapses that use P/Q-type voltage-gated calcium channels to release the neurotransmitter acetylcholine. Read More

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Engineered method for directional growth of muscle sheets on electrospun fibers.

J Biomed Mater Res A 2018 05 9;106(5):1165-1176. Epub 2018 Jan 9.

Department of Engineering Sciences, Institute of Biomedical Engineering, Old Road Campus Research Building, University of Oxford, Oxford, OX3 7DQ, United Kingdom.

Research on the neuromuscular junction (NMJ) and its function and development spans over a century. However, researchers are limited in their ability to conduct experimentation on this highly specialized synapse between motor neurons and muscle fibers, as NMJs are not easily accessible outside the body. The aim of this work is to provide a reliable and reproducible muscle sheet model for in vitro NMJ study. Read More

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Distinct Roles of Different Presynaptic and Postsynaptic NCAM Isoforms in Early Motoneuron-Myotube Interactions Required for Functional Synapse Formation.

J Neurosci 2018 01 24;38(2):498-510. Epub 2017 Nov 24.

Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4975,

The neural cell adhesion molecule (NCAM) is expressed both presynaptically and postsynaptically during neuromuscular junction formation. Genetic deletion in mice of all three isoforms (180, 140, and 120 kDa), or just the 180 isoform, suggested that different isoforms played distinct roles in synaptic maturation. Here we characterized in mice of either sex the earliest adhesive contacts between the growth cones of motoneurons and myotubes and their subsequent maturation into functional synapses in cocultures of motoneurons and myotubes, which expressed their normal complement of NCAM isoforms, or were lacking all isoforms either presynaptically or postsynaptically. Read More

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January 2018

Linker proteins restore basement membrane and correct -related muscular dystrophy in mice.

Sci Transl Med 2017 06;9(396)

Biozentrum, University of Basel, 4056 Basel, Switzerland.

-related muscular dystrophy ( MD or MDC1A) is the most frequent form of early-onset, fatal congenital muscular dystrophies. It is caused by mutations in , the gene encoding laminin-α2, the long arm of the heterotrimeric (α2, β1, and γ1) basement membrane protein laminin-211 (Lm-211). We establish that despite compensatory expression of laminin-α4, giving rise to Lm-411 (α4, β1, and γ1), muscle basement membrane is labile in MD biopsies. Read More

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Adeno-Associated Virus-Mediated Mini-Agrin Delivery Is Unable to Rescue Disease Phenotype in a Mouse Model of Limb Girdle Muscular Dystrophy Type 2I.

Am J Pathol 2017 Feb;187(2):431-440

McColl-Lockwood Laboratory for Muscular Dystrophy Research, Cannon Research Center, Carolinas Medical Center, Carolinas Healthcare System, Charlotte, North Carolina. Electronic address:

Agrin is a basement membrane-specific proteoglycan that can regulate orientation of cytoskeleton proteins and improve function of dystrophic skeletal muscle. In skeletal muscle, agrin binds with high affinity to laminin(s) and α-dystroglycan (α-DG), an integral part of the dystrophin-glycoprotein complex. Miniaturized forms of agrin (mAgrin) have been shown to ameliorate disease pathology in a laminin-α2 knockout mouse model of muscular dystrophy, acting as a link between α-DG and laminin(s). Read More

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February 2017

Laminin is instructive and calmodulin dependent kinase II is non-permissive for the formation of complex aggregates of acetylcholine receptors on myotubes in culture.

Matrix Biol 2017 01 10;57-58:106-123. Epub 2016 Dec 10.

Centre for Research in Neuroscience, and Dept. of Neurology, McGill University Health Centre, 1650, Cedar Ave., Montreal, Quebec, H3G 1A4, Canada. Electronic address:

Previous work has shown that myotubes cultured on laminin-coated substrates form complex aggregates of synaptic proteins that are similar in shape and composition to neuromuscular junctions (NMJs). Here we show that laminin instructs the location of complex aggregates which form only on the lower surface when laminin is coated onto culture dishes but over the entire cell when laminin is added in solution. Silencing of myotubes by agents that block electrical activity (tetrodotoxin, verapamil) or by inhibitors of calmodulin dependent kinase (CaMKII) render the myotube permissive for the formation of complex aggregates. Read More

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January 2017

Synthesis and deposition of basement membrane proteins by primary brain capillary endothelial cells in a murine model of the blood-brain barrier.

J Neurochem 2017 03 8;140(5):741-754. Epub 2016 Sep 8.

Laboratory of Neurobiology, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.

The brain vascular basement membrane is important for both blood-brain barrier (BBB) development, stability, and barrier integrity and the contribution hereto from brain capillary endothelial cells (BCECs), pericytes, and astrocytes of the BBB is probably significant. The aim of this study was to analyse four different in vitro models of the murine BBB for expression and possible secretion of major basement membrane proteins from murine BCECs (mBCECs). mBCECs, pericytes and glial cells (mainly astrocytes and microglia) were prepared from brains of C57BL/6 mice. Read More

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Roles of collagen Q in MuSK antibody-positive myasthenia gravis.

Chem Biol Interact 2016 Nov 24;259(Pt B):266-270. Epub 2016 Apr 24.

Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-Ku, Nagoya 466-8550, Japan.

The low-density lipoprotein receptor-related protein 4 (LRP4) and the muscle-specific receptor tyrosine kinase (MuSK) form a tetrameric protein complex on the postsynaptic membrane at the neuromuscular junction (NMJ). Binding of agrin to LRP4 triggers phosphorylation of MuSK. Activated MuSK drives clustering of acetylcholine receptor (AChR). Read More

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November 2016

Integrating Activities of Laminins that Drive Basement Membrane Assembly and Function.

Curr Top Membr 2015 25;76:1-30. Epub 2015 Jun 25.

Department of Pathology & Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA. Electronic address:

Studies on extracellular matrix proteins, cells, and genetically modified animals have converged to reveal mechanisms of basement membrane self-assembly as mediated by γ1 subunit-containing laminins, the focus of this chapter. The basic model is as follows: A member of the laminin family adheres to a competent cell surface and typically polymerizes followed by laminin binding to the extracellular adaptor proteins nidogen, perlecan, and agrin. Assembly is completed by the linking of nidogen and heparan sulfates to type IV collagen, allowing it to form a second stabilizing network polymer. Read More

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September 2016

Myasthenia gravis: subgroup classification and therapeutic strategies.

Lancet Neurol 2015 Oct;14(10):1023-36

Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.

Myasthenia gravis is an autoimmune disease that is characterised by muscle weakness and fatigue, is B-cell mediated, and is associated with antibodies directed against the acetylcholine receptor, muscle-specific kinase (MUSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane at the neuromuscular junction. Patients with myasthenia gravis should be classified into subgroups to help with therapeutic decisions and prognosis. Subgroups based on serum antibodies and clinical features include early-onset, late-onset, thymoma, MUSK, LRP4, antibody-negative, and ocular forms of myasthenia gravis. Read More

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October 2015

Flow Cytofluorimetric Analysis of Anti-LRP4 (LDL Receptor-Related Protein 4) Autoantibodies in Italian Patients with Myasthenia Gravis.

PLoS One 2015 18;10(8):e0135378. Epub 2015 Aug 18.

Institute of General Pathology, School of Medicine, Università Cattolica S. Cuore, Rome, Italy.

Background: Myasthenia gravis (MG) is an autoimmune disease in which 90% of patients have autoantibodies against the muscle nicotinic acetylcholine receptor (AChR), while autoantibodies to muscle-specific tyrosine kinase (MuSK) have been detected in half (5%) of the remaining 10%. Recently, the low-density lipoprotein receptor-related protein 4 (LRP4), identified as the agrin receptor, has been recognized as a third autoimmune target in a significant portion of the double sero-negative (dSN) myasthenic individuals, with variable frequency depending on different methods and origin countries of the tested population. There is also convincing experimental evidence that anti-LRP4 autoantibodies may cause MG. Read More

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Combination of agrin and laminin increase acetylcholine receptor clustering and enhance functional neuromuscular junction formation In vitro.

Dev Neurobiol 2016 May 21;76(5):551-65. Epub 2015 Aug 21.

ARC Centre of Excellence for Electromaterials Science, Intelligent Polymer Research Institute, University of Wollongong, Wollongong, NSW, 2522, Australia.

Clustering of acetylcholine receptors (AChR) at the postsynaptic membrane is a crucial step in the development of neuromuscular junctions (NMJ). During development and after denervation, aneural AChR clusters form on the sarcolemma. Recent studies suggest that these receptors are critical for guiding and initiating synaptogenesis. Read More

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Synaptic plasticity and cognitive function are disrupted in the absence of Lrp4.

Elife 2014 Nov 19;3:e04287. Epub 2014 Nov 19.

Graduate Program in Developmental Genetics, Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, NYU Medical Center, New York, United States.

Lrp4, the muscle receptor for neuronal Agrin, is expressed in the hippocampus and areas involved in cognition. The function of Lrp4 in the brain, however, is unknown, as Lrp4-/- mice fail to form neuromuscular synapses and die at birth. Lrp4-/- mice, rescued for Lrp4 expression selectively in muscle, survive into adulthood and showed profound deficits in cognitive tasks that assess learning and memory. Read More

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November 2014

Extracellular distribution of diffusible growth factors controlled by heparan sulfate proteoglycans during mammalian embryogenesis.

Philos Trans R Soc Lond B Biol Sci 2014 Dec;369(1657)

Department of Molecular Embryology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka Prefectural Hospital Organization, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan.

During mouse embryogenesis, diffusible growth factors, i.e. fibroblast growth factors, Wnt, bone morphogenetic protein and Hedgehog family members, emanating from localized areas can travel through the extracellular space and reach their target cells to specify the cell fate and form tissue architectures in coordination. Read More

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December 2014

Acetylcholine receptor (AChR) clustering is regulated both by glycogen synthase kinase 3β (GSK3β)-dependent phosphorylation and the level of CLIP-associated protein 2 (CLASP2) mediating the capture of microtubule plus-ends.

J Biol Chem 2014 Oct 17;289(44):30857-30867. Epub 2014 Sep 17.

Department of Cell Biology, Erasmus Medical Center, 3015 GE, Rotterdam, Netherlands,. Electronic address:

The postsynaptic apparatus of the neuromuscular junction (NMJ) traps and anchors acetylcholine receptors (AChRs) at high density at the synapse. We have previously shown that microtubule (MT) capture by CLASP2, a MT plus-end-tracking protein (+TIP), increases the size and receptor density of AChR clusters at the NMJ through the delivery of AChRs and that this is regulated by a pathway involving neuronal agrin and several postsynaptic kinases, including GSK3. Phosphorylation by GSK3 has been shown to cause CLASP2 dissociation from MT ends, and nine potential phosphorylation sites for GSK3 have been mapped on CLASP2. Read More

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October 2014

Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy.

Brain 2014 Sep 20;137(Pt 9):2429-43. Epub 2014 Jun 20.

5 Institute of Genetic Medicine, MRC Centre for Neuromuscular Diseases, Newcastle University, NE1 3BZ, Newcastle upon Tyne, UK

Congenital myasthenic syndromes are a clinically and genetically heterogeneous group of rare diseases resulting from impaired neuromuscular transmission. Their clinical hallmark is fatigable muscle weakness associated with a decremental muscle response to repetitive nerve stimulation and frequently related to postsynaptic defects. Distal myopathies form another clinically and genetically heterogeneous group of primary muscle disorders where weakness and atrophy are restricted to distal muscles, at least initially. Read More

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September 2014