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Development

Induction, assembly, maturation and maintenance of a postsynaptic apparatus

Key Points

  • The neuromuscular junction (NMJ) is one of the best models to study the induction, assembly, maturation and maintenance of a postsynaptic apparatus. The three most widely appreciated experimental advantages of the NMJ are its size, its simplicity and its accessibility.

  • Acetylcholine receptors (AChRs) are inserted at multiple points into the embryonic myotube membrane. As the NMJ develops, receptor density underneath the nerve increases and the number of extrasynaptic receptors is very small. Several mechanisms account for this phenomenon: some AChRs redistribute in the plane of the membrane, the metabolic stability of AChRs increases after clustering, myonuclei associated with the postsynaptic membrane become transcriptionally specialized to express AChRs, and AChR transcription is suppressed in non-synaptic nuclei. This reorganization depends on chemical influences from the motor nerve.

  • Several molecules that are responsible for postsynaptic reorganization have been identified. Their identification has led to a working model of how AChRs are clustered at the developing NMJ. In this model, the nerve releases a protein called agrin, which signals through a muscle-specific tyrosine kinase known as MuSK. MuSK then acts through an effector protein, rapsyn, to promote AChR clustering.

  • Although this basic model has received significant experimental support, there are other factors that affect NMJ development. Neuregulin and its ErbB receptor (another tyrosine kinase) also affect AChR clustering, but the interaction of these proteins with the agrin–MuSK–rapsyn pathway is unclear.

  • The embryonic NMJs are very different from the adult NMJs. The junction changes from a simple oval plaque to a pretzel-like set of branches, and the junctional membrane changes from a flat sheet to an invaginated surface with gutters and folds. Moreover, the composition of the basal lamina and the cytoskeletal apparatus change as the NMJ matures. Finally, a shift in AChR subunit composition leads to a change in their Ca2+ permeability, and ion- and ligand-gated channels segregate into discrete alternating domains. The mechanisms that underlie each of these transformations have only begun to be uncovered.

Abstract

The postsynaptic apparatus of the skeletal neuromuscular junction, like that of other synapses, contains a high-density patch of neurotransmitter receptors that is closely associated with a variety of extracellular, transmembrane and cytoplasmic proteins that have adhesive, structural and signalling roles. The postsynaptic apparatus is organized by signals from the presynaptic nerve terminal. It changes in shape, size and molecular architecture as it matures. Once mature, it can be maintained for the life of the organism, but has the capacity for remodelling in response to altered input. The molecular and cellular mechanisms that govern each of these stages are now being elucidated by a combination of microscopic and genetic methods, allowing the neuromuscular junction to serve as a model for smaller and less-accessible central synapses.

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Figure 1: The neuromuscular junction.
Figure 2: Clustering of AChRs as the neuromuscular junction forms.
Figure 3: Possible roles for neuregulin in postsynaptic differentiation.
Figure 4: Genetic analysis of early events in AChR clustering.
Figure 5: Maturation of the postsynaptic apparatus.
Figure 6: Turnover of AChRs in active, inactive and mutant muscles.

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Acknowledgements

The authors thank the National Institutes of Health for support, and R. M. Grady for figure 1.

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Correspondence to Joshua R. Sanes.

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DATABASES

GenBank

LocusLink

acetylcholinesterase

AChRs

agrin

ankyrin

α-bungarotoxin

Cdc42

dystrobrevin

dystroglycan

ErbB kinases

GA-repeat-binding protein

gephyrin

integrin α7

integrin αv

integrin β1

laminin α2

laminin α4

laminin α5

laminin β2

laminin γ1

MuSK

myogenin

neuregulin

pleiotrophin

Rac

rapsyn

α1-syntrophin

utrophin

OMIM

muscular dystrophy

Glossary

LAMININ

Glycoprotein that is the main constituent of basement membranes. It mediates the attachment, migration and organization of cells into tissues during development.

MIDKINE

A heparin-binding growth factor of the transforming growth factor-β superfamily. Midkine was originally described as being associated with tooth morphogenesis induced by epithelial–mesenchyme interactions.

PLEIOTROPHIN

A heparin-binding mitogenic protein that induces process extension in neurons and osteoblasts.

HEPARAN SULPHATE

A glycosaminoglycan that consists of repeated units of hexuronic acid and glucosamine residues. They usually attach to proteins through a xylose residue to form proteoglycans.

DOMINANT NEGATIVE

Describes a mutant molecule that is capable of forming a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

CONDITIONAL MUTAGENESIS

The generation of mutant animals in which the mutation can be selectively targeted to specific organs (or cell types within an organ) or induced at a specific developmental stage.

AUTOCRINE

An agent that acts on the cell that produced it.

RHO-GTPASE

A Ras-related GTPase that is involved in controlling the polymerization of actin.

FILOPODIA

Long, thin protrusions at the periphery of migrating cells and growth cones. They are rich in bundles of F-actin.

LECTINS

Sugar-binding proteins that tend to agglutinate cells. Concanavalin A is a widely used example.

MUSCULAR DYSTROPHY

A group of genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles, which control movement. The main forms of muscular dystrophy include myotonic, Duchenne and Becker.

SRC

A cytoplasmic tyrosine kinase that was first identified as a transforming oncogene in an avian retrovirus. This kinase is the prototypical kinase from which Src-homology regions were first described.

FLUORESCENCE RECOVERY AFTER PHOTOBLEACHING

A method used to measure the lateral diffusion of membrane elements. It requires tagging of the molecule of interest with a fluorescent marker, photobleaching of the label with a pulse of laser light, and a subsequent measure of the rate of fluorescence recovery into the bleached area as other labelled molecules move into it.

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Sanes, J., Lichtman, J. Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat Rev Neurosci 2, 791–805 (2001). https://doi.org/10.1038/35097557

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