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Current Opinion in Neurobiology Feb 1996Development of pre- and postsynaptic specializations at the vertebrate neuromuscular junction is affected by molecules concentrated in the extracellular matrix of the... (Review)
Review
Development of pre- and postsynaptic specializations at the vertebrate neuromuscular junction is affected by molecules concentrated in the extracellular matrix of the synaptic cleft. Agrin, laminin beta 2 and ARIA are the best characterized proteins known to be involved in particular aspects of synaptic differentiation. Recent advances in defining the domains of these molecules that are crucial for their synapse-organizing activity and their localization to synaptic basal lamina will help our understanding of the molecular mechanisms involved in synapse formation.
Topics: Agrin; Animals; Gene Expression; Laminin; Neuromuscular Junction
PubMed: 8794043
DOI: 10.1016/s0959-4388(96)80014-6 -
Cell and Tissue Research Nov 2021The extracellular matrix protein Agrin has been detected in chondrocytes and endosteal osteoblasts but its function in osteoblast differentiation has not been...
The extracellular matrix protein Agrin has been detected in chondrocytes and endosteal osteoblasts but its function in osteoblast differentiation has not been investigated yet. Thus, it is possible that Agrin contributes to osteoblast differentiation and, due to Agrin and wingless-related integration site (Wnt) sharing the same receptor, transmembrane low-density lipoprotein receptor-related protein 4 (Lrp4), and the crosstalk between Wnt and bone morphogenetic protein (BMP) signalling, both pathways could be involved in this Agrin-mediated osteoblast differentiation. Confirming this, Agrin and its receptors Lrp4 and α-dystroglycan (Dag1) were expressed during differentiation of osteoblasts from three different sources. Moreover, the disruption of Agrin impaired the expression of its receptors and osteoblast differentiation, and the treatment with recombinant Agrin slightly increase this process. In addition, whilst Agrin knockdown downregulated the expression of genes related to Wnt and BMP signalling pathways, the addition of Agrin had no effect on these genes. Altogether, these data uncover the contribution of Agrin to osteoblast differentiation and suggest that, at least in part, an Agrin-Wnt-BMP circuit is involved in this process. This makes Agrin a candidate as target for developing new therapeutic strategies to treat bone-related diseases and injuries.
Topics: 3T3 Cells; Agrin; Animals; Cell Differentiation; Cells, Cultured; Gene Expression Regulation; Humans; Mice; Mice, Inbred C57BL; Osteoblasts; Osteogenesis
PubMed: 34223979
DOI: 10.1007/s00441-021-03494-9 -
Cells Nov 2019The vertebrate skeletal neuromuscular junction (NMJ) has long served as a model system for studying synapse structure, function, and development. Over the last several... (Review)
Review
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. In place of a unitary mechanism for neuromuscular synapse formation, studies in both mice and zebrafish have led to the proposal that two mechanisms mediate synaptogenesis, with some synapses being induced by nerve contact while others involve the incorporation of prepatterned postsynaptic structures. Moreover, the current model also proposes that agrin can serve two functions, to induce synaptogenesis and to stabilize new synapses, once these are formed. This review examines the evidence for these propositions, and concludes that it remains possible that a single molecular mechanism mediates synaptogenesis at all NMJs, and that agrin acts as a stabilizer, while its role as inducer is open to question. Moreover, if agrin does not act to initiate synaptogenesis, it follows that as yet uncharacterized molecular interactions are required to play this essential inductive role. Several alternatives to agrin for this function are suggested, including focal pericellular proteolysis and integrin signaling, but all require experimental validation.
Topics: Agrin; Animals; Humans; Models, Animal; Neurogenesis; Neuromuscular Junction; Neurons; Synapses
PubMed: 31744142
DOI: 10.3390/cells8111448 -
Perspectives on Developmental... 1996Recent studies have documented important roles for heparan sulfate proteoglycans in the control of nervous system development. Agrin is an extracellular matrix protein... (Review)
Review
Recent studies have documented important roles for heparan sulfate proteoglycans in the control of nervous system development. Agrin is an extracellular matrix protein identified and named based on its involvement in the aggregation of acetylcholine receptors (AChRs) during synaptogenesis at the neuromuscular junction. Recent studies have demonstrated that agrin is a large extracellular heparan sulfate proteoglycan, with a molecular mass in excess of 500 kDa and a protein core of 220 kDa. Emerging evidence indicates that agrin's function is not limited to its role in AChR aggregation during synaptogenesis, as the majority of agrin expression occurs in the developing central nervous system, especially in developing axonal tracts. This review examines recent studies suggesting a role for agrin in the regulation of cell-cell interactions, most notably by its ability to interact with the neural cell adhesion molecule. In addition, other potential roles for the heparan sulfate chains of agrin during nervous system development are explored.
Topics: Agrin; Animals; Cell Communication; Extracellular Matrix Proteins; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Proteoglycans; Synapses
PubMed: 9117266
DOI: No ID Found -
Muscle & Nerve Sep 2020Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG).
INTRODUCTION
Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG).
METHODS
DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected.
RESULTS
Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years.
DISCUSSION
Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.
Topics: Adult; Agrin; Autoantibodies; Female; Humans; LDL-Receptor Related Proteins; Male; Middle Aged; Myasthenia Gravis; Prevalence; Symptom Assessment; United States
PubMed: 32483837
DOI: 10.1002/mus.26985 -
Current Opinion in Neurobiology Jun 1997Formation of the neuromuscular junction requires a series of reciprocal inductive interactions between the motor neuron and the muscle cell that culminate in the precise... (Review)
Review
Formation of the neuromuscular junction requires a series of reciprocal inductive interactions between the motor neuron and the muscle cell that culminate in the precise juxtaposition of a highly specialized presynaptic nerve terminal with a complex postsynaptic endplate on the muscle surface. Although nerve-derived agrin has long been thought to play a key role during neuromuscular junction formation, the molecular mechanisms underlying its actions are only now coming into focus, following the recent discovery that agrin acts via the MuSK receptor tyrosine kinase.
Topics: Agrin; Animals; Models, Biological; Muscle Proteins; Neuromuscular Junction; Receptors, Nicotinic; Signal Transduction
PubMed: 9232805
DOI: 10.1016/s0959-4388(97)80066-9 -
Trends in Cancer Apr 2017Agrin is utilized by motor neurons to stimulate the LRP4-MuSK receptor in muscles for neuromuscular junction (NMJ) formation. Recent studies of cancer have identified...
Agrin is utilized by motor neurons to stimulate the LRP4-MuSK receptor in muscles for neuromuscular junction (NMJ) formation. Recent studies of cancer have identified novel functions of the low-density lipoprotein receptor-related protein 4-muscle-specific kinase (LRP4-MuSK) pathway. Agrin may act as a mechanotransduction signal in the extracellular matrix (ECM) to coordinate the cross-talk between the LRP4-MuSK pathway and integrin-focal adhesion pathway. Ensuing Yes-associated protein (YAP) activation promotes hepatocellular carcinoma (HCC). Here, we discuss the implications of the converged pathways in NMJ formation and liver cancer.
Topics: Adaptor Proteins, Signal Transducing; Agrin; Animals; Cell Cycle Proteins; Humans; Mice; Neuromuscular Junction; Phosphoproteins; Signal Transduction; YAP-Signaling Proteins
PubMed: 28718435
DOI: 10.1016/j.trecan.2017.03.005 -
Muscle & Nerve Mar 2017The prevalence and characteristics of agrin and low-density lipoprotein-related receptor protein 4 (LRP4) antibody-positive amyotrophic lateral sclerosis (ALS) patients...
INTRODUCTION
The prevalence and characteristics of agrin and low-density lipoprotein-related receptor protein 4 (LRP4) antibody-positive amyotrophic lateral sclerosis (ALS) patients were studied.
METHODS
We tested 82 ALS patients and 59 controls for agrin and LRP4 antibodies using enzyme-linked immunoassay (ELISA).
RESULTS
We found that 13.8% of ALS patients had agrin antibodies, and 9.8% had LRP4 antibodies. Women with ALS are twice as likely as men to have antibodies. Agrin-positive ALS patients are younger than agrin-negative ALS patients.
CONCLUSIONS
Antibodies to agrin and LRP4 are found in ALS patients. It must be determined whether these antibodies are pathogenic. Because antibody-positive patients have upper as well as lower motor neuron findings, the antibodies' effects cannot be explained solely by their actions at the neuromuscular junction. A breakdown in interneuronal signaling may be the cause of ALS. Further research is needed to resolve this question. Muscle Nerve, 2016 Muscle Nerve 55: 430-432, 2017.
Topics: Age Factors; Agrin; Amyotrophic Lateral Sclerosis; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lipoproteins, LDL; Male; Sex Factors
PubMed: 27756107
DOI: 10.1002/mus.25438 -
Cell Death & Disease Mar 2024Sarcopenia, a progressive and prevalent neuromuscular disorder, is characterized by age-related muscle wasting and weakening. Despite its widespread occurrence, the...
Sarcopenia, a progressive and prevalent neuromuscular disorder, is characterized by age-related muscle wasting and weakening. Despite its widespread occurrence, the molecular underpinnings of this disease remain poorly understood. Herein, we report that levels of Agrin, an extracellular matrix (ECM) protein critical for neuromuscular formation, were decreased with age in the skeletal muscles of mice. The conditional loss of Agrin in myogenic progenitors and satellite cells (SCs) (Pax7 Cre:: Agrin flox/flox) causes premature muscle aging, manifesting a distinct sarcopenic phenotype in mice. Conversely, the elevation of a miniaturized form of Agrin in skeletal muscle through adenovirus-mediated gene transfer induces enhanced muscle capacity in aged mice. Mechanistic investigations suggest that Agrin-mediated improvement in muscle function occurs through the stimulation of Yap signaling and the concurrent upregulation of dystroglycan expression. Collectively, our findings underscore the pivotal role of Agrin in the aging process of skeletal muscles and propose Agrin as a potential therapeutic target for addressing sarcopenia.
Topics: Animals; Mice; Agrin; Muscle, Skeletal; Muscular Atrophy; Sarcopenia; Signal Transduction
PubMed: 38461287
DOI: 10.1038/s41419-024-06581-1 -
Severe congenital myasthenic syndromes caused by agrin mutations affecting secretion by motoneurons.Acta Neuropathologica Oct 2022Congenital myasthenic syndromes (CMS) are predominantly characterized by muscle weakness and fatigability and can be caused by a variety of mutations in genes required...
Congenital myasthenic syndromes (CMS) are predominantly characterized by muscle weakness and fatigability and can be caused by a variety of mutations in genes required for neuromuscular junction formation and maintenance. Among them, AGRN encodes agrin, an essential synaptic protein secreted by motoneurons. We have identified severe CMS patients with uncharacterized p.R1671Q, p.R1698P and p.L1664P mutations in the LG2 domain of agrin. Overexpression in primary motoneurons cultures in vitro and in chick spinal motoneurons in vivo revealed that the mutations modified agrin trafficking, leading to its accumulation in the soma and/or in the axon. Expression of mutant agrins in cultured cells demonstrated accumulation of agrin in the endoplasmic reticulum associated with induction of unfolded protein response (UPR) and impaired secretion in the culture medium. Interestingly, evaluation of the specific activity of individual agrins on AChR cluster formation indicated that when secreted, mutant agrins retained a normal capacity to trigger the formation of AChR clusters. To confirm agrin accumulation and secretion defect, iPS cells were derived from a patient and differentiated into motoneurons. Patient iPS-derived motoneurons accumulated mutant agrin in the soma and increased XBP1 mRNA splicing, suggesting UPR activation. Moreover, co-cultures of patient iPS-derived motoneurons with myotubes confirmed the deficit in agrin secretion and revealed a reduction in motoneuron survival. Altogether, we report the first mutations in AGRN gene that specifically affect agrin secretion by motoneurons. Interestingly, the three patients carrying these mutations were initially suspected of spinal muscular atrophy (SMA). Therefore, in the presence of patients with a clinical presentation of SMA but without mutation in the SMN1 gene, it can be worth to look for mutations in AGRN.
Topics: Agrin; Humans; Motor Neurons; Mutation; Myasthenic Syndromes, Congenital; Neuromuscular Junction
PubMed: 35948834
DOI: 10.1007/s00401-022-02475-8