Agrin isoforms and their role in synaptogenesis

doi:10.1016/0955-0674(92)90113-Q

Current Opinion in Cell Biology

Volume 4, Issue 5, October 1992, Pages 869-874

https://doi.org/10.1016/0955-0674(92)90113-Q Get rights and content

Abstract

Agrin is thought to mediate the motor neuron-induced aggregation of synaptic proteins on the surface of muscle fibers at neuromuscular junctions. Recent experiments provide direct evidence in support of this hypothesis, reveal the nature of agrin immunoreactivity at sites other than neuromuscular junctions, and have resulted in findings that are consistent with the possibility that agrin plays a role in synaptogenesis throughout the nervous system.

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The Agrin Hypothesis

Cited by (150)

MuSk function during health and disease
2020, Neuroscience Letters
Citation Excerpt :
Upon innervation MuSK is activated by the heparansulfate proteoglycan Agrin [29]. Agrin is produced by motor neurons and deposited in the basal lamina of the synaptic cleft [67]. Agrin does not bind MuSK directly but interacts with Lrp4, a member of the LDL receptor family [51,115].
The receptor tyrosine kinase MuSK (muscle-specific kinase) is the key signaling molecule during the formation of a mature and functional neuromuscular junction (NMJ). Signal transduction events downstream of MuSK activation induce both pre- and postsynaptic differentiation, which, most prominently, includes the clustering of acetylcholine receptors (AChRs) at synaptic sites. MuSK activation requires a complex interplay between its co-receptor Lrp4 (low-density lipoprotein receptor-related protein-4), the motor neuron-derived heparan-sulfate proteoglycan Agrin and the intracellular adaptor protein Dok-7. A tight regulation of MuSK kinase activity is crucial for proper NMJ development. Defects in MuSK signaling are the cause of muscle weakness as reported in congenital myasthenic syndromes and myasthenia gravis.
This review focuses on recent structure-based analyses of MuSK, Agrin, Lrp4 and Dok-7 interactions and their function during MuSK activation. Conclusions about the regulation of the MuSK kinase that were derived from molecular structures will be highlighted. In addition, the role of MuSK during development and disease will be discussed.
Induction of Anti-agrin Antibodies Causes Myasthenia Gravis in Mice
2018, Neuroscience
Citation Excerpt :
These results present evidence that N-agrin autoantibodies are pathogenic in causing MG, uncovered pathological mechanisms. Agrin has two isoforms, M-agrin and N-agrin, which are specifically expressed in muscles and motor neurons, respectively (McMahan et al., 1992; Ruegg et al., 1992). Containing an 8-amino acid insert at the Z site (Z8) that is missing in M-agrin, N-agrin has up to 1000-fold greater AChR clustering activity, compared to M-agrin.
Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction (NMJ). Most cases of MG are caused by autoantibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) and low-density lipoprotein receptor-related protein 4 (LRP4). Recent studies have identified anti-agrin antibodies in MG patients lacking these three antibodies (i.e., triple negative MG). Agrin is a basal lamina protein that has two isoforms. Neural agrin (N-agrin) binds to LRP4 to activate MuSK to induce AChR clusters and is thus critical for NMJ formation. We demonstrate that mice immunized with N-agrin showed MG-associated symptoms including muscle weakness, fragmented and distorted NMJs. These effects were not observed in mice injected with muscle agrin (M-agrin), an isoform that is inactive in inducing AChR clusters. Treatment with anti-N-agrin, but not anti-M-agrin, antibodies reduced agrin-induced AChR clusters in muscle cells. Together, these observations suggest that agrin antibodies may be play a role in MG pathogenesis.
Heart Regeneration 4.0: Matrix Medicine
2017, Developmental Cell
Citation Excerpt :
Using a neonatal mouse heart model in which the regenerative capacity is lost by 7 days of age (P7) (Porrello et al., 2011), the team showed that the cell-free ECM fragments from P1 hearts induce the normally non-proliferative P7 CMs in vitro. Using mass spectrometry, they identified Agrin, a proteoglycan known to be critical for maintaining functional neuromuscular junctions (McMahan et al., 1992), present in the P1 but not in P7 ECM and further showed that Agrin is sufficient to promote P1 and P7 CM proliferation in vitro (Figure 1A). To determine the role of Agrin in vivo, Bassat et al. (2017) utilized the cardiac mesoderm driver Mesp1-Cre to conditionally delete Agrin (Agrin-cKO) in the murine heart and assessed the maturity and turnover of CMs at P1.
The long and short of non-coding RNAs during post-natal growth and differentiation of skeletal muscles: Focus on lncRNA and miRNAs
2016, Differentiation
Citation Excerpt :
Maturation of myofibre innervation: Another key stage of post-natal muscle growth is the maturation of the NMJ. Agrin protein is involved in the formation of NMJs (Burden, 2011): agrin induces and stabilises proteins accumulating on the post-synaptic muscle membrane (sarcolemma), including acetylcholine receptors (AChRs), and can be neural or muscular in origin (Burgess et al., 1999; McMahan et al., 1992). Total Agrn mRNA in the somatosensory cortices of mouse brains is high post-natally, but decreases to low adult levels by 3 weeks post-birth (Li et al., 1997), similar to the timing of down-regulation of agrin RNA levels in our muscle study, with high RNA levels at birth that decreased between 2 and 4 weeks during the period of NMJ maturation.
Post-natal growth of skeletal muscle is a dynamic process involving proliferation and fusion of myoblasts with elongating myofibres (hyperplasia of myonuclei) until 3 weeks post-natally in mice, with ongoing differentiation and further increases in myofibre size mostly by hypertrophy until about 12 weeks of age. The expression of mRNAs that control these events are well described, but little is known about the in vivo roles of non-coding RNAs (ncRNAs), including both microRNAs (miRNAs) and the lesser-studied long non-coding RNAs (lncRNAs). We analysed expression patterns for a broad range of lncRNAs (including Neat1, Malat1, Sra, Meg3, LncMyoD and linc-MD1), miRNAs and mRNAs in muscles of normal male C57Bl/6J mice at 2 days and 2, 4, 6 and 12 weeks after birth. These post-natal patterns were compared with expression of these RNAs during classic C2C12 myogenesis and differentiation in tissue culture. This overview of RNAs during post-natal skeletal muscle growth provides a novel focus on ncRNAs during this often overlooked growth period, with many potential applications to normal muscle growth in humans and livestock, and to childhood muscle disorders.
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
2014, Journal of Biological Chemistry
Citation Excerpt :
The major presynaptic organizer of postsynaptic differentiation at the neuromuscular junction (NMJ)4 is agrin (1–3), a heparan sulfate proteoglycan secreted from the motor nerve terminal and acting through its receptor/effector LRP4/MuSK in the muscle fiber membrane (4, 5).
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. How CLASP2 phosphorylation regulates MT capture at the NMJ and how this controls the size of AChR clusters are not yet understood. To examine this, we used myotubes cultured on agrin patches that induce AChR clustering in a two-dimensional manner. We show that expression of a CLASP2 mutant, in which the nine GSK3 target serines are mutated to alanine (CLASP2–9XS/9XA) and are resistant to GSK3β-dependent phosphorylation, promotes MT capture at clusters and increases AChR cluster size, compared with myotubes that express similar levels of wild type CLASP2 or that are noninfected. Conversely, myotubes expressing a phosphomimetic form of CLASP2 (CLASP2–8XS/D) show enrichment of immobile mutant CLASP2 in clusters, but MT capture and AChR cluster size are reduced. Taken together, our data suggest that both GSK3β-dependent phosphorylation and the level of CLASP2 play a role in the maintenance of AChR cluster size through the regulated capture and release of MT plus-ends.
Deficiency of skeletal muscle Agrin contributes to the pathogenesis of age-related sarcopenia in mice
2024, Cell Death and Disease

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Agrin isoforms and their role in synaptogenesis

Abstract

Neuron

J Neurosci

Neuron

Cell

J Cell Biol

J Cell Biol

Cell

J Exp Biol

Identification of Agrin, a Synaptic Organizing Protein from Torpedo Electric Organ

J Cell Biol

Molecules in Basal Lamina that Direct the Formation of Synaptic Specialization at Neuromuscular Junctions

Dev Neurosci

The Agrin Hypothesis