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  • Review Article
  • Published:

New insights into the roles of agrin

Nature Reviews Molecular Cell Biology volume 4, pages 295–309 (2003)Cite this article

Key Points

  • The heparan sulphate proteoglycan agrin, which is encoded by a single gene, is known to be a key regulator of the formation of postsynaptic structures at the neuromuscular junction (NMJ).

  • Alternative messenger RNA splicing gives rise to several agrin isoforms that differ at their amino and/or their carboxyl termini. Whereas splicing at the amino terminus might affect agrin's localization in various tissues, carboxy-terminal splicing regulates agrin's ability to induce postsynapses.

  • Agrin's ability to induce postsynaptic structures at the NMJ requires the muscle-specific receptor tyrosine kinase MuSK. Agrin- and MuSK-deficient mice have similar phenotypes and die at birth. Biochemical studies indicate that MuSK does not bind agrin directly, but rather is a signalling component of a larger protein complex, the components of which have not yet been identified.

  • Agrin is also expressed in the brain but its exact role in this organ is not known.

  • The recently described role of agrin in T-cell activation indicates that agrin's function might be regulated by glycosylation, and that agrin might be involved in the aggregation of lipid rafts at the immunological synapse.

  • At the NMJ, agrin also activates the Rho-family of small GTPases, indicating that the cytoskeleton has an active role in the formation of postsynapses. The adaptor protein Dishevelled seems to regulate the specificity and efficiency of this activation.

  • The agrin splice variant that is inactive in inducing postsynapses at the NMJ has recently been shown to globally affect the cytoskeleton of skeletal muscle through costamere organization. Moreover, a miniature version of this isoform ameliorates the dystrophic phenotype in mice that lack the laminin α2 chain, which is an animal model for merosin-deficient congenital muscle dystrophy.

  • Further studies that are focused on agrin glycosylation, its role in the aggregation of lipid rafts and cytoskeletal organization might unravel some of the missing links in our knowledge of the formation of synapses in the nervous and immune systems.

Abstract

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.

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Figure 1: Structural similarities between neuronal and immunological synapses.
Figure 2: Postsynaptic differentiation at the neuromuscular junction.
Figure 3: Formation of an immunological synapse.
Figure 4: Stabilization of AChR aggregates in the innervated muscle.
Figure 5: Signalling activated by agrin-B/z+ at the NMJ.
Figure 6: The laminin/integrin–agrin–α-dystroglycan network.
Figure 7: Agrin and lipid rafts at the NMJ.

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Acknowledgements

We would like to thank J.L. Bixby, T. Meier & A. Rolink for their critical reading of this manuscript. We are grateful to A. Devor and J.M. Fritschy for providing figure 1a, and to F. Rupp for providing figure 1c. We would also like to apologize to all of our colleagues whose contributions to the work summarized in this review could not be cited because of space constraints. The work in our laboratory is supported by the Kanton Basel-Stadt, the Swiss National Science Foundation, the Swiss Foundation for Research on Muscle Diseases and the Muscular Dystrophy Association USA.

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Authors and Affiliations

  1. Department of Pharmacology/Neurobiology, Biozentrum, University of Basel, Klingelbergstrasse 70, Basel, CH-4056, Switzerland

    Gabriela Bezakova & Markus A. Ruegg

Authors
  1. Gabriela Bezakova
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  2. Markus A. Ruegg
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Correspondence to Markus A. Ruegg.

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DATABASES

LocusLink

Dvl

ephrin

ErbB

FAK

GABP

neurexin

PAK

Swiss-Prot

agrin

Cdc42

CD4

CD44

cortactin

CREB

dystroglycan

laminin α2

Lck

MuSK

rapsyn

utrophin

FURTHER INFORMATION

Markus A. Ruegg's laboratory

Leiden Muscular Dystrophy pages

Neuromuscular Disease Center

The Wnt gene Homepage

Glossary

ANTIGEN-PRESENTING CELL

A cell that is specialized in the generation of epitopes that are presented through major histocompatibility complex (MHC) I or II to T lymphocytes.

NEUROMUSCULAR JUNCTION

(NMJ). The place of contact between the terminal of a motor neuron and the membrane of a muscle fibre. Nerve impulses are transmitted across the gap by diffusion of a transmitter.

MAJOR HISTOCOMPATIBILITY COMPLEX

(MHC). A cluster of genes on human chromosome 6 or mouse chromosome 17 that encode MHC molecules. These molecules are the most polymorphic in the genome and are the ones recognized by T lymphocytes during transplant rejection. They encode a family of cellular antigens that help the immune system to recognize self from non-self.

SYNAPTIC CLEFT

The extracellular gap of a synapse that separates the outer membrane of the presynaptic nerve terminal from the postsynaptic membrane of the receiving cell.

BASAL LAMINA

A thin sheet of extracellular matrix molecules, which consists mainly of collagens, laminins, nidogen and proteoglycans and forms a region between cells and adjacent connective tissue. It has an important influence on the organization of tissues.

MYOTUBE

A multinucleated cell that is formed by the fusion of proliferating myoblasts and is characterized by the presence of certain muscle-specific marker proteins.

SCHWANN CELL

A non-neuronal cell that produces myelin and ensheaths axons and presynaptic nerve terminals in the peripheral nervous system.

MYOBLAST

An embryonic precursor cell that is still able to proliferate and can fuse to form myotubes.

SUPERIOR CERVICAL GANGLION

(SCG). An aggregate of neurons of the sympathetic nervous system that are innervated by preganglionic neurons of the spinal cord. Postganglionic targets are the blood vessels, glands and pilomotor muscles of the head and neck.

CREB

(cyclic AMP response-element-binding protein). A transcription factor that functions in glucose homeostasis and growth-factor-dependent cell survival, and has also been implicated in learning and memory.

C-FOS

An immediate-early gene that belongs to the Fos family, which includes fosB, fra-1 and fra-2. These proteins form heterodimers with members of the Jun family and form transcription factors that bind to the AP-1 DNA element. Fos–Jun complexes have been implicated in many diverse cellular responses including learning and memory in the brain.

MICROVASCULATURE

Very small blood vessels. In the brain, these fine cerebral vessels and capillaries maintain the blood–brain barrier and are the point of exchange for nutrients, electrolytes and metabolites between neural tissue and blood.

AMYLOID PLAQUE

A deposition of amyloid β peptide in the brain that is a hallmark of Alzheimer's disease, a neurodegenerative disease that affects the elderly with a primary symptom of dementia.

DENDRITIC ARBORIZATION

The ability of neurons to form an elaborate, arbor-like network of dendrites (receiving part of a neuron).

SRC FAMILY KINASES

(SFKs). Kinases that belong to the Src family of tyrosine kinases, the largest of the non-receptor tyrosine kinases families. SFKs include Src, Yes, Fyn, Lck, Lyn, Blk, Hck, Fgr and Yrk.

NEURAMINIDASE

An enzyme that catalyses the cleavage of neuraminic acid from oligosaccharide chains of glycoproteins and glycolipids. As these residues are usually terminal, neuraminidases are generally exo-enzymes, although an endoneuraminidase is known.

GPI-ANCHOR

The function of this post-translational glycosylphosphatidylinositol modification is to attach proteins to the exoplasmic leaflet of membranes, possibly to specific domains therein. The anchor is made of one molecule of phosphatidylinositol to which a carbohydrate chain is linked through the C-6 hydroxyl of the inositol, and is linked to the protein through an ethanolamine phosphate moiety.

PLANAR-CELL POLARITY

The polarization of cells in the plane of the epithelium. This phenomenon is best studied in Drosophila but is also found in vertebrates where it affects aspects of skin development and features of inner-ear development.

RHO FAMILY GTPASES

Ras-related GTPases that are involved in controlling the polymerization of actin.

DOMINANT-NEGATIVE

A defective protein that retains interaction abilities and so distorts or competes with normal proteins.

RUFFLE

A cytoplasmic projection at the leading edge of a migrating cell that has lifted from the substratum. Molecules that are involved in actin cytoskeletal rearrangement are enriched in ruffles.

MICROVILLUS

A small, finger-like projection (1–2 μm long and 100 nm wide) that occurs on the exposed surfaces of epithelial cells to maximize the surface area.

FILOPODIUM

A finger-like exploratory cell extension that is found in crawling cells and growth cones.

COSTAMERE

A myofibril attachment site that forms one of the main linkage sites of the skeletal muscle cell, encircling the cell and connecting the Z-discs to the sarcolemma.

INTEGRINS

A large group of heterodimeric transmembrane adhesion receptors for several extracellular matrix proteins such as fibronectin, vitronectin and laminin.

TRAILING EDGE

The region of the cell with a high concentration of adhesion receptors, ezrin–radixin–moesin (ERM) proteins, myosin II, tubulin cytoskeleton and protein kinase C, that has a pivotal role in cell adhesion and facilitates cell migration.

LEADING EDGE

The thin margin of a lamellipodium spanning the area of the cell from the plasma membrane to about 1 μm back into the lamellipodium.

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Bezakova, G., Ruegg, M. New insights into the roles of agrin. Nat Rev Mol Cell Biol 4, 295–309 (2003). https://doi.org/10.1038/nrm1074

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