Agrin and Synaptic Laminin Are Required to Maintain Adult Neuromuscular Junctions

Samuel, Melanie A.; Valdez, Gregorio; Tapia, Juan Carlos; Lichtman, Jeff W.; Sanes, Joshua R.

doi:10.1371/journal.pone.0046663

Cited by 100 publications

(137 citation statements)

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“…The muscle-specific receptor tyrosine kinase MuSK and the motor neuron-derived MuSK activator agrin play essential roles in the formation and maintenance of NMJs in the central region of each myotube, and their mutation has been reported in some types of CMSs (5)(6)(7)(8)(9)(10)(11)(12)(13). Before motor innervation during normal development, or in genetically engineered mouse embryos that lack motor neurons, AChR transcripts and proteins are expressed and clustered only in the central region of the skeletal muscle in a manner dependent on MuSK (1,14).…”

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confidence: 99%

“…Consistent with this, agrin-deficient mice show muscle prepatterning, but fail to form NMJs due to rapid dispersal of AChR clusters upon motor innervation (14). In addition, because postnatal loss of MuSK or agrin causes disassembly of NMJs (6,11), agrin-dependent MuSK activation is believed to be essential for the maintenance of NMJs. However, molecular mechanisms underlying this agrin-dependent NMJ maintenance remain to be studied.…”

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The MuSK activator agrin has a separate role essential for postnatal maintenance of neuromuscular synapses

Tezuka

Inoue

Hoshi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The motoneural control of skeletal muscle contraction requires the neuromuscular junction (NMJ), a midmuscle synapse between the motor nerve and myotube. The formation and maintenance of NMJs are orchestrated by the muscle-specific receptor tyrosine kinase (MuSK). Motor neuron-derived agrin activates MuSK via binding to MuSK's coreceptor Lrp4, and genetic defects in agrin underlie a congenital myasthenic syndrome (an NMJ disorder). However, MuSK-dependent postsynaptic differentiation of NMJs occurs in the absence of a motor neuron, indicating a need for nerve/agrin-independent MuSK activation. We previously identified the muscle protein Dok-7 as an essential activator of MuSK. Although NMJ formation requires agrin under physiological conditions, it is dispensable for NMJ formation experimentally in the absence of the neurotransmitter acetylcholine, which inhibits postsynaptic specialization. Thus, it was hypothesized that MuSK needs agrin together with Lrp4 and Dok-7 to achieve sufficient activation to surmount inhibition by acetylcholine. Here, we show that forced expression of Dok-7 in muscle enhanced MuSK activation in mice lacking agrin or Lrp4 and restored midmuscle NMJ formation in agrin-deficient mice, but not in Lrp4-deficient mice, probably due to the loss of Lrp4-dependent presynaptic differentiation. However, these NMJs in agrin-deficient mice rapidly disappeared after birth, and postsynaptic specializations emerged ectopically throughout myotubes whereas exogenous Dok-7-mediated MuSK activation was maintained. These findings demonstrate that the MuSK activator agrin plays another role essential for the postnatal maintenance, but not for embryonic formation, of NMJs and also for the postnatal, but not prenatal, midmuscle localization of postsynaptic specializations, providing physiological and pathophysiological insight into NMJ homeostasis. neuromuscular junction | postsynaptic specialization | Dok-7 | Lrp4

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confidence: 99%

mentioning

confidence: 99%

The MuSK activator agrin has a separate role essential for postnatal maintenance of neuromuscular synapses

Tezuka

Inoue

Hoshi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Basal lamina fills the synaptic cleft and contain synaptic laminins, which serve as ligands for nerve terminal and skeletal muscle fibre thus facilitating anchorage and signaling between both regions, which is essential for normal development and maintenance of the NMJ (Sanes et al, 1978;Sanes, 1995;Patton et al, 2001;Knight et al, 2003;Nishimune et al, 2004;Samuel et al, 2012) (Figure 1.1).…”

Section: The Structure Of the Neuromuscular Junctionmentioning

confidence: 99%

“…Signaling and adhesion molecules such as the synaptic laminins found within the basal lamina, are suggested to be involved in the organisation and maintenance of key components of the pre-and postsynaptic specialisations (Noakes et al, 1995a;Patton et al, 1997;Knight et al, 2003;Nishimune et al, 2004;Carlson et al, 2010;Samuel et al, 2012). The synaptic laminin chains (α, β and γ) form the laminin heterotrimers that include laminin-221 (α2β2γ1), laminin-421 (α4β2γ1) and laminin-521 (α5β2γ1) Patton et al, 1997;Patton, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Laminin-β2 chain is involved in the development and maturation of the NMJ via its interaction and subsequent involvement in the developmental switch of the voltage-gated calcium channels (Nishimune et al, 2004;Chand et al, 2015). Laminin-α4 is suggested to be important for the maintenance of the NMJ, with the loss of this laminin resulting in premature ageing (Samuel et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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The role of synaptic laminins-α4 and -β2 in maturation and maintenance of the neuromuscular synapse

Lee¹

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The proper development, maturation and maintenance of the neuromuscular junction (NMJ) are critical for ensuring efficient neurotransmission. Proteins found within the basal lamina of the synaptic cleft, namely the laminins family, are heavily involved in maintaining normal structure and function of the NMJ. In particular, individual laminin chains such as laminin-β2, -α4 and -α5 play essential roles in organisation and maintenance of the NMJ. These laminin chains interact together to form three synapse specific laminin heterotrimers; laminin-221 (α2β2γ1), laminin-421 (α4β2γ1) and laminin-521 (α5β2γ1).Laminin-β2 is the common laminin chain found in each of these synapse specific laminin heterotrimers. In-vitro it has been shown to play a key role in the organisation of the presynaptic elements at the NMJ via its interaction and clustering of the N-and P/Q-type voltage-gated calciums (VGCCs). During development of the NMJ, both N-and P/Q-type VGCCs are involved in mediating neurotransmitter release. As the NMJ matures, P/Q-type becomes the dominant channel involved in release while N-type takes on the role of fine-tuning calcium influx. Laminin-α4, on the other hand, ensures proper alignment of presynaptic active zones to postjunctional folds at the NMJ, with its loss resulting in misalignment of these specialisations. Furthermore, this laminin chain has been shown to be involved in the maintenance of the NMJ with the observation of premature ageing features at 6 months of age (6MO) in laminin-α4 deficient mice (lama4 NMJs.In conclusion, this thesis has identified the significant roles laminins-α4 and -β2 play at the NMJ during development, maturation and maintenance. Results suggest that laminin-β2 is not only an important regulator of the presynaptic maturation through the switching of VGCCs and clustering of P/Q-type VGCCs, but also equally important for maturation of the postsynaptic apparatus. Ipropose that laminin-β2 is important for the maturation of each component at the NMJ. The altered responses in transmission properties presented by aged wild-type NMJs which resembled adult lama4 -/-, preceded by altered expression of laminin-α4 chain, strongly suggest that laminin-α4 is not only important for maintaining proper alignment of pre-to postsynaptic NMJ, but also essentially important for maintaining a healthy adult NMJ. Finally, I observed early alterations in expression of laminin-α4 at the NMJs in diseased mouse model of ALS prior to any appearance of neuromotor impairment, suggesting a potential involvement of laminins in NMJ degeneration associated with neuromuscular disorders such as ALS.ii

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Collagen XIII and Other ECM Components in the Assembly and Disease of the Neuromuscular Junction

Heikkinen

Härönen

Norman

et al. 2019

The Anatomical Record

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Alongside playing structural roles, the extracellular matrix (ECM) acts as an interaction platform for cellular homeostasis, organ development, and maintenance. The necessity of the ECM is highlighted by the diverse, sometimes very serious diseases that stem from defects in its components. The neuromuscular junction (NMJ) is a large peripheral motor synapse differing from its central counterparts through the ECM included at the synaptic cleft. Such synaptic basal lamina (BL) is specialized to support NMJ establishment, differentiation, maturation, stabilization, and function and diverges in molecular composition from the extrasynaptic ECM. Mutations, toxins, and autoantibodies may compromise NMJ integrity and function, thereby leading to congenital myasthenic syndromes (CMSs), poisoning, and autoimmune diseases, respectively, and all these conditions may involve synaptic ECM molecules. With neurotransmission degraded or blocked, muscle function is impaired or even prevented. At worst, this can be fatal. The article reviews the synaptic BL composition required for assembly and function of the NMJ molecular machinery through the lens of studies primarily with mouse models but also with human patients. In‐depth focus is given to collagen XIII, a postsynaptic‐membrane‐spanning but also shed ECM protein that in recent years has been revealed to be a significant component for the NMJ. Its deficiency in humans causes CMS, and autoantibodies against it have been recognized in autoimmune myasthenia gravis. Mouse models have exposed numerous details that appear to recapitulate human NMJ phenotypes relatively faithfully and thereby can be readily used to generate information necessary for understanding and ultimately treating human diseases. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc.

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Agrin and Synaptic Laminin Are Required to Maintain Adult Neuromuscular Junctions

Cited by 100 publications

References 61 publications

The MuSK activator agrin has a separate role essential for postnatal maintenance of neuromuscular synapses

The MuSK activator agrin has a separate role essential for postnatal maintenance of neuromuscular synapses

The role of synaptic laminins-α4 and -β2 in maturation and maintenance of the neuromuscular synapse

Collagen XIII and Other ECM Components in the Assembly and Disease of the Neuromuscular Junction

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