BIOLOGICAL OVERVIEW

Neurexins are components of septate junctions playing a role in cell adhesion; in vertebrates they are components of synapses, playing a potential role in axon guidance and innervation. Neurexin functions in the establishment of an association of the internal cytoskeleton with the cell surface, and can function, at least in vertebrates, in transducing extracellular events to the inside of the cell via a specialized intracellular kinase.

Drosophila Neurexin, termed Neurexin IV (NRX) because of its homology to a human homolog, is the first member of the neurexin family isolated in a nonmammlian species. Three Neurexins in vertebrates have large extracellular domains with multiple laminin G motifs (see Drosophila Laminin A) and epidermal growth factor repeats, and are expressed exclusively in the brain.

Neurexin functions in association with septate junctions. Epithelial cells contain specialized junctions that have been classified at the ultrastructural level. Different types of junctions fulfill a variety of functions: some mediate cell communication (gap junctions and chemical synapses), others anchor cells to the extracellular matrix or adjacent cells (adherens junctions, focal contacts, and desmosomes), and still others serve as selective-permeability barriers, separating apical and basal boundaries (tight junctions and septate junctions). Septate junctions (SJs) in Drosophila are common to all epithelia and can be subdivided into two types: smooth SJs (sSJs) found in gut endoderm and Malpighian tubules, and pleated SJs (pSJs) found in ectodermally derived epithelia, i.e., glial sheaths, epidermis, trachea, salivary glands, ectodermal parts of the alimentary canal, and imaginal discs. Neurexin is involved in formation of pSJs, and appear to be responsible for distinguishing sSJs and pSJs (Tepass, 1994 and Baumgartner, 1996).

Other molecules found at septate junctions include the cell adhesion protein Fasciclin III, as well as Expanded, and Coracle. Both Expanded and Coracle are members of the 4.1 family of proteins that includes mammalian ezrin, radixin and moesin. The 4.1 family proteins physically bind cytoskeletal elements (Fehon, 1994 and Woods, 1996). The protein Discs-large contains PDZ-domains, and a domain with homology to guanylate kinases, suggesting a role in cell signaling. DLG protein is required for junction structure, cell polarity, and proliferation control in Drosophila epithelia. (Woods, 1996).

In vertebrates, glial tight junctions serve the purpose of providing a selective-diffusion barrier to ions, protecting the nervous system from contact with the environment. Such junctions are virtually absent in insects, and it is thought that pleated septate junctions serve this barrier function. Each SJ may confer partial impermeability, so that together they form a barrier that protects neurons from high potassium ion concentration in the hemolymph of insects. Neurexin mutants are defective in providing the protective barrier shielding the fly's nervous system from high potassium ion levels. Nrx mutants are paralyzed, and electrophysiological studies indicate that the lack if NRX iin glial-glial SJs causes a breakdown in the blood-brain barrier. Electron microscopy demonstrates that Nrx mutants lack the ladder-like intracellular septa characteristic of pleated septate junctions. Similar breakdown occurs with gliotactin mutation (Baumgartner, 1996 and Auld, 1995).

In addition, mutation of Drosophila Nrx results in mislocalization of Coracle at SJs and causes dorsal closure defects similar to those observed in coracle mutants.

Drosophila NRX does not localize to synapses as does vertebrate Neurexins, and Drosophila NRX does not play a role in synaptic function. It is clear that vertebrate Neurexins have assumed a role not found in Drosophila. Alternative splicing of vertebrate neurexins represents a potential mechanism for creating a large number of cell surface receptors expressed by specific subsets of neurons, perhaps functioning to determine highly specific axon guidance and innervation (Puschel, 1995). Neurexins are also involved in cell signaling. The mammalian protein CASK is an intracellular protein kinase that interacts with different neurexins. CASK is composed of an N-terminal Ca2+, calmodulin-dependent protein kinase and a C-terminal region that is similar to the intercellular junction proteins homologous to Drosophila Discs large 1. CASK is enriched in synaptic plasma membranes in the brain, but is also detectable at low levels in other tissues (Hata, 1996).

Human Neurexin IV, in contrast to Neurexins I, II and III, contains an N-terminal discoidin domain. In human NRX IV and Drosophila Neurexin, the discoidin domain is found in place of the N-terminal laminin domain and an EGF-like repeat found in the other human Neurexin proteins. The discoidin motif is thought to be a carbohydrate binding domain characteristic of lectins. Thus it is thought that Neurexin plays a role in cell adhesion or adherence to extracellular matrix, binding carbohydrates on the surface of adjacent cells or constituting a part matrix components surrounding cells (Valencia, 1989).

The human Neurexin IV is expressed in brain, kidney and lung. The Neurexins, including the Drosophila protein, contain a cytoplasmic domain homologous to glycophorin C, a protein required for anchoring protein 4.1 (Drosophila homolog: Coracle) to the inner aspect of cell surfaces (Baumgartner, 1996 and references).

GENE STRUCTURE

Exons - at least 4

PROTEIN STRUCTURE

Amino Acids - 1283

Structural Domains

The initiation methionine is followed by a secretory signal sequence. There is a transmembrane-spanning domain close to the C-terminus. The protein shows a domain structure like that of vertebrate neurexins. Drosophila NRX contains five laminin G domains (see Drosophila Laminin) and two EGF modules. The only difference between Drosophila and vertebrate proteins is that an N-terminal 6th laminin G domain and a third EGF module in vertebrate neurexins is replaced by a discoidin domain, thought to represent a lectin-binding domain. The similarity to neurexins is highest in the EGF modules and lower in the laminin G domain. In addition, the intracellular domain of NRX displays 68% similarity to the intracellular domain of glycophorin C. A human Neurexin found in brain, kidney and lung, humIV, contains an N-terminal DS domain. It is suggested that the Drosophila protein is a homolog of the human gene, and indicates the existence of a fourth neurexin in vertebrates whose expression is not limited to the nervous system. There is no indication of alternative splicing in the Drosophila gene (Baumgartner, 1996).

date revised: 30 Dec 96 

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