The VASE exon downregulates the neurite growth-promoting activity of NCAM 140

Abstract

Axonal growth, guidance and synapse formation are controlled by receptors on neuronal growth cones that can recognize positive and inhibitory cues in the local microenvironment. Four well characterized receptor systems are known that recognize the growth-promoting activities associated with the extracellular matrix and the membranes of cells such as astrocytes, muscle cells and Schwann cells; these are the integrins and the homophilically binding cell adhesion molecules neural-cell adhesion molecule (NCAM), N-cadherin and L1 (refs 5-12). Alternative splicing generates 20-30 isoforms of NCAM and these can also be differentially glycosylated. There are two sites where alternative splicing changes the extracellular structure of membrane-bound NCAM and one of these (the MSD1 region) does not obviously affect function. Here we report that the variable alternatively spliced exon (VASE) in immunoglobulin domain 4 downregulates the neurite outgrowth-promoting activity of NCAM. The high level of VASE expression in the adult central as compared with peripheral nervous system could contribute to the poor regenerative capacity of the former.

PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth

“…7A). The VASE-excluding isoform of NCAM-140 (VASE À ) promotes neurite outgrowth, while the VASE-including isoform (VASE + ) inhibits neurite outgrowth (Doherty et al 1992). The embryonic brain mainly expresses VASE À with gradual ascendancy until final dominance of VASE + expression toward adulthood, except in regions such as the olfactory bulb, where reformation of synapses and turnover of neurons continue (Small and Akeson 1990).…”

“…The AS of VASE determines the inclusion or exclusion of the fourth Ig domain and alters the homophilic binding of NCAM-140 (Lahrtz et al 1997). The VASE À isoform of NCAM-140 stimulateswhile VASE + inhibits-neurite outgrowth (Doherty et al 1992;Liu et al 1993;Saffell et al 1994).…”

Expression and alternative splicing of the neural cell adhesion molecule NCAM in human granulosa cells during luteinization

“…It is conceivable that altered NCAM forms could account for various degrees of cellular 'adhesiveness', and that the change in the amounts of NCAM isoforms with or without exon VASE, when granulosa cells undergo luteinization, could affect NCAM function and cell behavior. Such a regulatory influence has been observed in neurons, where VASE down-regulated the neurite outgrowth-promoting effect of NCAM [9,34].…”

“…The alternatively spliced exon VASE is close to the NCAM domain that mediates cell--cell adhesion [8]. The biological relevance of VASE expression still remains obscure, however, in the nervous system, VASE has been shown to down-regulate the neurite growth-promoting effect of NCAM [9]. NCAM mRNAs containing VASE were also present in rodent endocrine tissues and cells [10].…”

Organization of the Neurofascin Gene and Analysis of Developmentally Regulated Alternative Splicing

“…For example, for the extracellular domains of NCAM, an alternatively spliced exon, termed VASE, introduces additional amino acid residues within the fourth Ig-like domain (50 -52). The inclusion of the VASE exon alters the neurite outgrowth promoting activity (53,54) and might regulate the signaling of NCAM (5). In the FGFR 1, the alternate usage of two exons encoding two different COOH-terminal halves of the third Ig-like domain modulate the affinity for one of its ligands, bFGF (55).…”