Characterization of a Highly Conserved Human Homolog to the Chicken Neural Cell Surface Protein Bravo/Nr-CAM That Maps to Chromosome Band 7q31

doi:10.1006/geno.1996.0385

Genomics

Volume 35, Issue 3, 1 August 1996, Pages 456-465

https://doi.org/10.1006/geno.1996.0385 Get rights and content

Abstract

The neuronal cell adhesion molecule Bravo/Nr-CAM is a cell surface protein of the immunoglobulin (Ig) superfamily and is closely related to the L1/NgCAM and neurofascin molecules, all of which contain six immunoglobulin domains, five fibronectin repeats, a transmembrane region, and an intracellular domain. Chicken Bravo/Nr-CAM has been shown to interact with other cell surface molecules of the Ig superfamily and has been implicated in specific pathfinding roles of axonal growth cones in the developing nervous system. We now report the characterization of cDNA clones encoding the human Bravo/Nr-CAM protein, which, like its chicken homolog, is composed of six V-like Ig domains and five fibronectin type III repeats. The human Bravo/Nr-CAM homolog also contains a transmembrane and intracellular domain, both of which are 100% conserved at the amino acid level compared to its chicken homolog. Overall, the human Bravo/Nr-CAM homolog is 82% identical to the chicken Bravo/Nr-CAM amino acid sequence. Independent cDNAs encoding four different isoforms were also identified, all of which contain alternatively spliced variants around the fifth fibronectin type III repeat, including one isoform that had been previously identified for chicken Bravo/Nr-CAM. Northern blot analysis reveals one mRNA species of approximately 7.0 kb in adult human brain tissue. Fluorescencein situhybridization maps the gene for human Bravo/Nr-CAM to human chromosome 7q31.1–q31.2. This chromosomal locus has been previously identified as containing a tumor suppressor candidate gene commonly deleted in certain human cancer tissues.

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Cited by (32)

The role of NrCAM in neural development and disorders-Beyond a simple glue in the brain
2012, Molecular and Cellular Neuroscience
Citation Excerpt :
The first three exons and introns are spread over 200 kb, which may contain regulatory sequences for the expression of NrCAM, ensuring specific spatial and temporal expression patterns (Williams et al., 2006). NrCAM undergoes extensive splicing events that produce several different isoforms (Ishiguro et al., 2006; Lane et al., 1996; Wang et al., 1998). The most prominent splicing is a 93 amino acid deletion in the fifth Fn type III repeat, resulting in the prevalent form of NrCAM in the brain that has only four, instead of five Fn type III repeats.
NrCAM is a neuronal cell adhesion molecule of the L1 family of immunoglobulin super family. It plays a wide variety of roles in neural development, including cell proliferation and differentiation, axon growth and guidance, synapse formation, and the formation of the myelinated nerve structure. NrCAM functions in cell adhesion and modulates signaling pathways in neural development through multiple molecular interactions with guidance and other factors. Alterations in NrCAM structure/expression are associated with psychiatric disorders such as autism and drug addiction and with tumor progression. The mechanisms of NrCAM participation in development and how these might be perturbed in disorders are reviewed.
Gene expression profiling of major depression and suicide in the prefrontal cortex of postmortem brains
2008, Neuroscience Research
Genome-wide gene expression analysis using DNA microarray has a great advantage to identify the genes or specific molecular cascades involved in mental diseases, including major depression and suicide. In the present study, we conducted DNA microarray analysis of major depression using postmortem prefrontal cortices. The gene expression patterns were compared between the controls and subjects with major depression. As a result, 99 genes were listed as the differentially expressed genes in major depression, of which several genes such as FGFR1, NCAM1, and CAMK2A were of interest. Gene ontology analysis suggested an overrepresentation of genes implicated in the downregulation or inhibition of cell proliferation. The present results may support the hypothesis that major depression is associated with impaired cellular proliferation and plasticity. Comparison between the controls and suicide victims with major depression, bipolar disorder, or schizophrenia was also conducted in the present study. Two genes, CAD and ATP1A3, were differentially expressed in the three comparisons in the same direction. Interestingly, these two genes were also included in the differentially expressed 99 genes in major depression. It may be worth investigating the genes in relation to suicide or major depression.
The complete sequence of the human locus for NgCAM-related cell adhesion molecule reveals a novel alternative exon in chick and man and conserved genomic organization for the L1 subfamily
2001, Gene
NrCAM is one member of the L1 subfamily of cell surface recognition molecules implicated in nervous system development and function. Here we report the complete sequence of the human NRCAM locus. The gene comprises 34 exons and shows extensive conservation of exon/intron structure compared to L1, suggesting a common evolutionary ancestor. By human–chick sequence comparison we identified exons not previously found in mammalian NRCAM mRNAs. One of these encodes a premature stop codon that would give rise to an isoform of NRCAM lacking ankyrin-binding capacity. The availability of the complete sequence will allow an investigation of the potential role of these splice variants, and examination of the regulatory elements controlling NRCAM expression as well as the relationship of NRCAM to disorders involving 7q.
Alternative mRNA splicing in colon cancer causes loss of expression of neural cell adhesion molecule
2001, Surgery
Citation Excerpt :
A secreted form of NCAM has been identified that results from insertion of a stop codon after exon 12.31 Bravo, an adhesion molecule with 6 immunoglobulins and 5 FN-III domains, also exhibits numerous splice variants with insertions between the 2 membranes proximal to the FN-III domains.32 Other molecules similar to NCAM , such as those deleted in colon cancer, L1,33 contactin,34 and fasciclin,35 have a variable number of FN-III repeat elements between the immunoglobulin domains and the plasma membrane.
Background. The neural cell adhesion molecule (NCAM) has numerous isoforms resulting from alternative splicing of mRNA. The 3 major isoforms found in adult tissue are (1) a 120-kDa protein that is linked to the plasma membrane by glycosylphosphatidylinositol; (2) a 140-kDa form that has a transmembrane component and a cytoplasmic tail with unknown function; and (3) a 180-kDa isoform that has an intracellular protein that binds the cytoskeleton. NCAM is capable of homotypic binding and therefore plays a role in cell-cell adhesion for cells expressing the 180-kDa isoform by anchoring groups of cells into epithelial sheets. NCAM-180 is the isoform found in colonocytes, and loss of expression is associated with clinically aggressive colon cancers. Methods. Western blotting and reverse transcriptase-polymerase chain reaction were used to screen commercially available cell lines for NCAM-180 expression. For cell-line pairs with differential NCAM-180 expression, exon analysis was performed with reverse transcriptase-polymerase chain reaction to determine where the molecule was spliced, culminating in failed expression. These results were confirmed with exon analysis in colon cancers harvested at the time of laparotomy. Results. Analysis of a SW480 cell line (derived from a patient's primary colon cancer lesion) revealed NCAM-180 expression, whereas no expression was found in the SW620 cell line (derived from a metastatic lesion from the same patient). Exon analysis of NCAM mRNA transcripts from SW620 revealed that the transcripts were truncated after exon 12. This region correlates to an area between 2 fibronectin-III domains on the NCAM protein. Conclusions. The most common site for NCAM alternative splicing is between the 2 fibronectin-III domains corresponding to the border between exons 12 and 13 of the NCAM gene. Loss of NCAM-180 expression in aggressive colon carcinoma results from a splice defect in the same area, which may result in defective intracellular adhesion between colonocytes. (Surgery 2001;130:834-43.)
Nr-CAM promotes neurite outgrowth from peripheral ganglia by a mechanism involving axonin-1 as a neuronal receptor
1999, Developmental Biology
Nr-CAM is a neuronal cell adhesion molecule (CAM) belonging to the immunoglobulin superfamily that has been implicated as a ligand for another CAM, axonin-1, in guidance of commissural axons across the floor plate in the spinal cord. Nr-CAM also serves as a neuronal receptor for several other cell surface molecules, but its role as a ligand in neurite outgrowth is poorly understood. We studied this problem using a chimeric Fc-fusion protein of the extracellular region of Nr-CAM (Nr-Fc) and investigated potential neuronal receptors in the developing peripheral nervous system. A recombinant Nr-CAM-Fc fusion protein, containing all six Ig domains and the first two fibronectin type III repeats of the extracellular region of Nr-CAM, retains cellular and molecular binding activities of the native protein. Injection of Nr-Fc into the central canal of the developing chick spinal cordin ovoresulted in guidance errors for commissural axons in the vicinity of the floor plate. This effect is similar to that resulting from treatment with antibodies against axonin-1, confirming that axonin-1/Nr-CAM interactions are important for guidance of commissural axons through a spatially and temporally restricted Nr-CAM positive domain in the ventral spinal cord. When tested as a substrate, Nr-Fc induced robust neurite outgrowth from dorsal root ganglion and sympathetic ganglion neurons, but it was not effective for tectal and forebrain neurons. The peripheral but not the central neurons expressed high levels of axonin-1 bothin vitroandin vivo.Moreover, antibodies against axonin-1 inhibited Nr-Fc-induced neurite outgrowth, indicating that axonin-1 is a neuronal receptor for Nr-CAM on these peripheral ganglion neurons. The results demonstrate a role for Nr-CAM as a ligand in axon growth by a mechanism involving axonin-1 as a neuronal receptor and suggest that dynamic changes in Nr-CAM expression can modulate axonal growth and guidance during development.
Alternative splicing of human NrCAM in neural and nonneural tissues
1998, Molecular and Cellular Neurosciences
Neural cell adhesion molecule NrCAM exists in a variety of isoforms as a result of alternative splicing of individual exons during RNA processing. In this report we demonstrate that many of the alternative splicing events described for chick are conserved in man and describe a novel variant of NrCAM cDNA. Furthermore, we show that NrCAM is expressed at significant levels outside the nervous system; in particular in pancreas, adrenal glands, and placenta and that expression in both brain and other tissues is accompanied by a very variable pattern of exon utilization in fetal and adult cells.

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^☆: Sequence data from this article have been deposited with the GenBank/EMBL Data Libraries under Accession No. U55258.

¹: To whom correspondence should be addressed. Telephone: (818) 395-4909. Fax: (818) 449-0756. E-mail: [email protected].

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Regular ArticleCharacterization of a Highly Conserved Human Homolog to the Chicken Neural Cell Surface Protein Bravo/Nr-CAM That Maps to Chromosome Band 7q31☆

Abstract

Regular Article
Characterization of a Highly Conserved Human Homolog to the Chicken Neural Cell Surface Protein Bravo/Nr-CAM That Maps to Chromosome Band 7q31☆