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Developmental Neurobiology Aug 2014Neuromuscular junction (NMJ) is a cholinergic synapse where motor neurons elicit muscle contraction. Agrin and its coreceptors LRP4 and MuSK are critical for vertebrate... (Review)
Review
Neuromuscular junction (NMJ) is a cholinergic synapse where motor neurons elicit muscle contraction. Agrin and its coreceptors LRP4 and MuSK are critical for vertebrate NMJ formation. This paper reviews recent evidence for Wnts and Wnt signaling molecules in NMJ formation including a possible retrograde mechanism by muscle β-catenin. We also present data that Wnt3a, 7a, 8a and 10b could inhibit agrin-mediated AChR clustering. Together with the stimulating effect of Wnt9a, 9b, 10b, 11 and 16 on AChR clustering in the absence of agrin, these results suggest diverse roles for Wnt ligands in NMJ development.
Topics: Agrin; Animals; Cell Differentiation; Humans; Neuromuscular Junction; Synapses; Vertebrates; Wnt Signaling Pathway
PubMed: 24838312
DOI: 10.1002/dneu.22190 -
Molecules (Basel, Switzerland) Aug 2017Acetylcholinesterase (AChE) and agrin, a heparan-sulfate proteoglycan, reside in the basal lamina of the neuromuscular junction (NMJ) and play key roles in cholinergic... (Review)
Review
Acetylcholinesterase (AChE) and agrin, a heparan-sulfate proteoglycan, reside in the basal lamina of the neuromuscular junction (NMJ) and play key roles in cholinergic transmission and synaptogenesis. Unlike most NMJ components, AChE and agrin are expressed in skeletal muscle and α-motor neurons. AChE and agrin are also expressed in various other types of cells, where they have important alternative functions that are not related to their classical roles in NMJ. In this review, we first focus on co-cultures of embryonic rat spinal cord explants with human skeletal muscle cells as an experimental model to study functional innervation in vitro. We describe how this heterologous rat-human model, which enables experimentation on highly developed contracting human myotubes, offers unique opportunities for AChE and agrin research. We then highlight innovative approaches that were used to address salient questions regarding expression and alternative functions of AChE and agrin in developing human skeletal muscle. Results obtained in co-cultures are compared with those obtained in other models in the context of general advances in the field of AChE and agrin neurobiology.
Topics: Acetylcholinesterase; Agrin; Animals; Cells, Cultured; Coculture Techniques; GPI-Linked Proteins; Humans; Models, Biological; Muscle Cells; Muscle, Skeletal; Musculoskeletal Physiological Phenomena; Neuromuscular Junction; Rats; Spinal Cord
PubMed: 28846617
DOI: 10.3390/molecules22091418 -
Neurochemistry International Nov 2012Development of the neuromuscular junction (NMJ) requires secretion of specific isoforms of the proteoglycan agrin by motor neurons. Secreted agrin is widely expressed in... (Review)
Review
Development of the neuromuscular junction (NMJ) requires secretion of specific isoforms of the proteoglycan agrin by motor neurons. Secreted agrin is widely expressed in the basal lamina of various tissues, whereas a transmembrane form is highly expressed in the brain. Expression in the brain is greatest during the period of synaptogenesis, but remains high in regions of the adult brain that show extensive synaptic plasticity. The well-established role of agrin in NMJ development and its presence in the brain elicited investigations of its possible role in synaptogenesis in the brain. Initial studies on the embryonic brain and neuronal cultures of agrin-null mice did not reveal any defects in synaptogenesis. However, subsequent studies in culture demonstrated inhibition of synaptogenesis by agrin antisense oligonucleotides or agrin siRNA. More recently, a substantial loss of excitatory synapses was found in the brains of transgenic adult mice that lacked agrin expression everywhere but in motor neurons. The mechanisms by which agrin influences synapse formation, maintenance and plasticity may include enhancement of excitatory synaptic signaling, activation of the "muscle-specific" receptor tyrosine kinase (MuSK) and positive regulation of dendritic filopodia. In this article I will review the evidence that agrin regulates synapse development, plasticity and signaling in the brain and discuss the evidence for the proposed mechanisms.
Topics: Agrin; Animals; Central Nervous System; Mice; Mice, Knockout; Neuronal Plasticity; Signal Transduction; Synapses
PubMed: 22414531
DOI: 10.1016/j.neuint.2012.02.028 -
Investigative Ophthalmology & Visual... May 2020To investigate the effect and mechanism of Agrin on limbal stem cell proliferation and corneal wound healing.
PURPOSE
To investigate the effect and mechanism of Agrin on limbal stem cell proliferation and corneal wound healing.
METHODS
Limbal stem cells were isolated and treated with different concentrations of Agrin. CCK-8 and cell proliferation markers (Ki67 and pH3) were detected to evaluate cell numbers or proliferative potential of limbal stem cells. The corneal epithelium wound model was induced by debridement of central corneal epithelial, and the effects of Agrin on limbal stem cell proliferation and corneal epithelial wound healing rate were determined.
RESULTS
Agrin promoted the proliferation of cultured limbal stem cells in vitro and increased the expression level of p63α rather than keratin 12. Furthermore, Agrin accelerated the wound healing rate of corneal epithelium through activating limbal stem cell proliferation in vivo. In terms of mechanism, Agrin could facilitate the dephosphorylation of Yap1, which contributed to the nuclear translocation of Yap1 and expression of Cyclin D1, and subsequently promoted proliferation of limbal stem cells.
CONCLUSIONS
Agrin promotes the proliferation of limbal stem cells and accelerates the healing rate of corneal wound through Hippo-Yap signaling pathway.
Topics: Adaptor Proteins, Signal Transducing; Agrin; Animals; Cell Cycle Proteins; Cell Proliferation; Cells, Cultured; Corneal Injuries; Epithelium, Corneal; Hippo Signaling Pathway; Limbus Corneae; Mice, Inbred C57BL; Models, Animal; Protein Serine-Threonine Kinases; Signal Transduction; Stem Cells; Wound Healing; YAP-Signaling Proteins
PubMed: 32392315
DOI: 10.1167/iovs.61.5.7 -
Neurorehabilitation and Neural Repair Dec 2020Agrin is a proteoglycan that aggregates nicotinic acetylcholine receptors (AChRs) on neuromuscular junctions and takes part in synaptogenesis in the development of the...
BACKGROUND
Agrin is a proteoglycan that aggregates nicotinic acetylcholine receptors (AChRs) on neuromuscular junctions and takes part in synaptogenesis in the development of the central nervous system. However, its effects on neural repair and synaptogenesis after stroke are still unclear.
OBJECTIVE
This study aimed to investigate the effects of agrin on neural repair and synaptogenesis after stroke and the effects of exercise on this process in vivo and in vitro.
METHODS
Exercise with gradually increased intensity was initiated at 1 day after middle cerebral artery occlusion (MCAO) for a maximum of 14 days. Neurological deficit scores and foot fault tests were used to assess the behavioral recovery. Western blotting, immunofluorescence, and electron microscopic images were used to detect the expression of agrin, synaptogenesis-related proteins, and synaptic density in vivo. In vitro, the ischemic neuron model was established via oxygen-glucose deprivation (OGD). The lentivirus overexpressed agrin and CREB inhibitor were used to investigate the mechanism by which agrin promoted synaptogenesis.
RESULTS
Exercise promoted behavioral recovery and this beneficial role was linked to the upregulated expression of agrin and increased synaptic density. Overexpressed agrin promoted synaptogenesis in OGD neuron, CREB inhibitor downregulated the expression of agrin and hampered synaptogenesis in cultured neurons.
CONCLUSIONS
These results indicated that exercise poststroke improved the recovery of behavioral function after stroke. Synaptogenesis was an important and beneficial factor, and agrin played a critical role in this process and could be a potential therapeutic target for the treatment of stroke and other nervous system diseases.
Topics: Agrin; Animals; Behavior, Animal; Disease Models, Animal; Infarction, Middle Cerebral Artery; Male; Neurogenesis; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Recovery of Function; Stroke; Synapses; Up-Regulation
PubMed: 33135566
DOI: 10.1177/1545968320969939 -
Nature Reviews. Molecular Cell Biology Apr 2003The heparan sulphate proteoglycan agrin is expressed as several isoforms in various tissues. Agrin is best known as a crucial organizer of postsynaptic differentiation... (Review)
Review
The heparan sulphate proteoglycan agrin is expressed as several isoforms in various tissues. Agrin is best known as a crucial organizer of postsynaptic differentiation at the neuromuscular junction, but it has recently also been implicated in the formation of the immunological synapse, the organization of the cytoskeleton and the amelioration of function in diseased muscle. So the activities of agrin might be of broader significance than previously anticipated.
Topics: Agrin; Alternative Splicing; Animals; Genetic Variation; Humans; Nervous System Physiological Phenomena; Neuromuscular Junction; Neurons; Protein Isoforms; Synapses; Transcription, Genetic
PubMed: 12671652
DOI: 10.1038/nrm1074 -
Neurosurgery Jul 1995One of the foremost challenges to repairing damage after stroke, trauma, or disease is the regeneration of synaptic connections between neurons. Here, we consider recent... (Review)
Review
One of the foremost challenges to repairing damage after stroke, trauma, or disease is the regeneration of synaptic connections between neurons. Here, we consider recent strides in our understanding of the molecular basis of synapse formation and regeneration. We will focus on the protein agrin, a key player in synaptogenesis at neuromuscular junctions and perhaps at central nervous system synapses as well. Insights into agrin and its receptor could guide the development of rational therapies to combat neuronal degeneration. We will also consider recent surprising and provocative data linking the mechanisms of synapse formation and the cellular pathology in Duchenne muscular dystrophy.
Topics: Agrin; Animals; Central Nervous System; Cytoskeletal Proteins; Dystroglycans; Humans; Membrane Glycoproteins; Muscular Dystrophies; Nerve Regeneration; Neuromuscular Junction; Neurons; Receptors, Growth Factor; Synapses
PubMed: 8587694
DOI: 10.1227/00006123-199507000-00011 -
Frontiers in Immunology 2021This study aimed to establish a cell-based assay (CBA) for the detection of agrin antibodies (Agrin-Ab) to explore the clinical features of agrin antibody-positive...
This study aimed to establish a cell-based assay (CBA) for the detection of agrin antibodies (Agrin-Ab) to explore the clinical features of agrin antibody-positive Chinese patients with myasthenia gravis (Agrin-MG). We developed a CBA based on the human full-length agrin protein expressed in HEK293T cells for the reliable and efficient detection of Agrin-Ab. Clinical data and serum samples were collected from 1948 MG patients in 26 provinces in China. The demographic and clinical features of Agrin-MG patients were compared with those of other MG patient subsets. Eighteen Agrin-MG cases were identified from 1948 MG patients. Nine patients were Agrin-Ab positive, and nine were AChR-Ab and Agrin-Ab double-positive (Agrin/AChR-MG). Eleven (61.11%) patients were males older than 40 years of age. The initial symptom in 13 (81.25%) cases was ocular weakness. Occasionally, the initial symptom was limb-girdle weakness (two cases) or bulbar muscle weakness (one case). Agrin-MG patients demonstrated slight improvement following treatment with either acetylcholinesterase inhibitor or prednisone; however, the combination of the two drugs could effectively relieve MG symptoms. In China, Agrin-MG demonstrated seropositivity rates of 0.92%. These patients were commonly middle-aged or elderly men. The patients usually presented weakness in the ocular, bulbar, and limb muscles, which may be combined with thymoma. These patients have more severe diseases, although the combination of pyridostigmine and prednisone was usually effective in relieving symptoms.
Topics: Age of Onset; Aged; Agrin; Autoantibodies; Autoantigens; China; Cholinesterase Inhibitors; Female; Geography, Medical; HEK293 Cells; Humans; Male; Middle Aged; Muscle Weakness; Myasthenia Gravis; Prednisone; Recombinant Proteins; Thymoma; Thymus Neoplasms
PubMed: 34956185
DOI: 10.3389/fimmu.2021.753247 -
Journal of Neurocytology 2003Agrin is a heparan sulfate proteoglycan, which plays an essential role in the development and maintenance of the neuromuscular junction. Agrin is a stable component of... (Review)
Review
Agrin is a heparan sulfate proteoglycan, which plays an essential role in the development and maintenance of the neuromuscular junction. Agrin is a stable component of the synaptic basal lamina and strong evidence supports the hypothesis that agrin directs the formation of the postsynaptic apparatus, including aggregates of AChRs, and junctional folds. Changes in the distribution of agrin during synaptic remodeling, denervation and reinnervation reveal that agrin can be quickly and efficiently removed from the synaptic basal lamina in a regulated manner. In order to fully understand this mechanism we sought to identify those molecules that were responsible for the removal of agrin. Matrix Metalloproteinases (MMPs) were the most likely molecules since MMPs are involved in the regulation of the pericellular space, including the cleavage of matrix proteins. In particular, MMP3 has been shown to be effective in cleaving heparan sulfate proteoglycans. Antibodies to MMP3 recognize molecules concentrated in the extracellular matrix of perisynaptic Schwann cells. MMP3 specific phylogenic compounds reveal that active MMP3 is localized to the neuromuscular junction. Purified recombinant MMP3 can directly cleave agrin, and it can also remove agrin from synaptic basal lamina. MMP3 activity is itself regulated as activation of MMP3 is lost in denervated muscles. MMP3 null mutant mice have altered neuromuscular junction structure and function, with increased AChRs, junctional folds and agrin immunoreactivity. Altogether these results support the hypothesis that synaptic activity induces the activation of MMP3, and the activated MMP3 removes agrin from the synaptic basal lamina.
Topics: Action Potentials; Agrin; Animals; Basement Membrane; Humans; Matrix Metalloproteinase 3; Synapses
PubMed: 15034275
DOI: 10.1023/B:NEUR.0000020631.69804.f5 -
Biotechnology Advances 2008Agrin and neuregulin are broadly expressed molecules that have significant developmental roles. Here we review the diverse temporal and spatial expression patterns and... (Review)
Review
Agrin and neuregulin are broadly expressed molecules that have significant developmental roles. Here we review the diverse temporal and spatial expression patterns and functions of these molecules and the impact that dysregulation may have on a number of disease states. Many know agrin as a modulator of synaptogenesis and the neuregulins for their prominent role in breast cancer; this review elaborates on many of the other proposed functions for these molecules both in the nervous system and elsewhere. In several instances we discuss the possible use of agrin, neuregulin and related molecules as therapeutic agents.
Topics: Agrin; Animals; Heart Failure; Humans; Models, Biological; Muscular Dystrophy, Duchenne; Neoplasms; Neuregulins
PubMed: 18222620
DOI: 10.1016/j.biotechadv.2007.11.003