Meerabux, J. M. et al. Human netrin-G1 isoforms show evidence of differential expression. Genomics 86, 112-116

Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Genomics (Impact Factor: 2.28). 08/2005; 86(1):112-6. DOI: 10.1016/j.ygeno.2005.04.004
Source: PubMed


The recently identified netrins-G1 and -G2 form a distinct subgroup within the UNC-6/netrin gene family of axon guidance molecules. In this study, we determined the size and structure of the exon/intron layout of the human netrin-G1 (NTNG1) and -G2 (NTNG2) genes. Northern analysis of both genes showed limited nonneuronal but wide brain expression, particularly for NTNG2. Reverse transcriptase PCR detected nine alternatively spliced isoforms including four novel variants of NTNG1 from adult brain. A semiquantitative assay established that major expression was restricted to isoforms G1c, G1d, G1a, and G1e in the brain and to G1c in the kidney. There is also evidence of developmental regulation of these isoforms between fetal and adult brain. In conclusion, NTNG1 may use alternative splicing to diversify its function in a developmentally and tissue-specific manner.

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Available from: Shigeyoshi Itohara,
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    • "Ntng1 and Ntng2 are clearly expressed in distinct neuronal subsets in a complementary manner [5,6] and have different roles in distinct neuronal circuits [12,13]. The differential expression patterns are highly conserved in primates such as marmosets and macaque [14], and also likely in humans [15]. Human genetics studies have detected single nucleotide polymorphisms in both NTNG1 and NTNG2 in association with schizophrenia [16-18] and rearrangements in NTNG1 in a patient with Rett syndrome [19,20]. "
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    ABSTRACT: Higher brain function is supported by the precise temporal and spatial regulation of thousands of genes. The mechanisms that underlie transcriptional regulation in the brain, however, remain unclear. The Ntng1 and Ntng2 genes, encoding axonal membrane adhesion proteins netrin-G1 and netrin-G2, respectively, are paralogs that have evolved in vertebrates and are expressed in distinct neuronal subsets in a complementary manner. The characteristic expression patterns of these genes provide a part of the foundation of the cortical layer structure in mammals. We used gene-targeting techniques, bacterial artificial chromosome (BAC)-aided transgenesis techniques, and in vivo enhancer assays to examine transcriptional mechanisms in vivo to gain insight into how the characteristic expression patterns of these genes are acquired. Analysis of the gene expression patterns in the presence or absence of netrin-G1 and netrin-G2 functional proteins allowed us to exclude the possibility that a feedback or feedforward mechanism mediates their characteristic expression patterns. Findings from the BAC deletion series revealed that widely distributed combinations of cis-regulatory elements determine the differential gene expression patterns of these genes and that major cis-regulatory elements are located in the 85-45 kb upstream region of Ntng2 and in the 75-60 kb upstream region and intronic region of Ntng1. In vivo enhancer assays using 2-kb evolutionarily conserved regions detected enhancer activity in the distal upstream regions of both genes. The complementary expression patterns of Ntng1 and Ntng2 are determined by transcriptional cis-regulatory elements widely scattered in these loci. The cis-regulatory elements characterized in this study will facilitate the development of novel genetic tools for functionally dissecting neural circuits to better understand vertebrate brain function.
    Molecular Brain 03/2014; 7(1):19. DOI:10.1186/1756-6606-7-19 · 4.90 Impact Factor
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    • "interact with either netrinG1 or G2, but binds to the receptor protein tyrosine phosphatase LAR family of transmembrane proteins (Woo et al, 2009). NGL1 and NGL2 proteins as well as NetrinG1 and G2 exhibit complimentary patterns of expression in the developing and mature brain (Nakashiba et al, 2002; Meerabux et al, 2005). These observations raised the possibility that their differential expression and selective binding might form a molecular code contributing to the specificity of neuronal circuits. "
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    ABSTRACT: NetrinG proteins and NetrinG ligands (NGLs) are adhesive ligand/receptor pairs that influence axon outgrowth and synaptogenesis. In humans, NetrinG mutations are correlated with developmental disorders of cognition, including schizophrenia and Rett syndrome. In this issue of The EMBO Journal, Seiradake et al (2011) report the crystal structures of NetrinGs and NGLs separately and in complex, revealing a remarkable modularity underlying the molecular specificity of NetrinG/NGL interactions. © 2011 European Molecular Biology Organization | All Rights Reserved.
    The EMBO Journal 11/2011; 30(21):4342-4. DOI:10.1038/emboj.2011.375 · 10.43 Impact Factor
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    • "Northern blot analysis indicates that mouse netrin-G1 and netrin-G2 mRNAs are predominantly expressed in brain, with weak expression of netrin-G2 in other tissues including heart, lung, and kidney (Nakashiba et al., 2000; Nakashiba et al., 2002; Yin et al., 2002). Expression of splice variants of human netrin-G1 mRNAs is regulated in a development-and tissuedependent manner (Meerabux et al., 2005). In situ hybridization indicates that netrin-G1 and netrin-G2 mRNAs exhibit mainly nonoverlapping expression patterns in brain regions (Nakashiba et al., 2000, 2002; Yin et al., 2002). "
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    ABSTRACT: Synaptic adhesion molecules are known to participate in various steps of synapse development including initial contacts between dendrites and axons, formation of early synapses, and their maturation and plastic changes. Notably, a significant subset of synaptic adhesion molecules associates with synaptic scaffolding proteins, suggesting that they may act in concert to couple trans-synaptic adhesion to molecular organization of synaptic proteins. Here, we describe an emerging group of synaptic adhesion molecules that directly interact with the abundant postsynaptic scaffold PSD-95, which include neuroligins, NGLs, SALMs, and ADAM22, and discuss how these proteins and PSD-95 act together to regulate synaptic development. PSD-95 may be one of the central organizers of synaptic adhesion that recruits diverse proteins to sites of synaptic adhesion, promotes trans-synaptic signaling, and couples neuronal activity with changes in synaptic adhesion.
    Progress in Neurobiology 04/2008; 84(3):263-83. DOI:10.1016/j.pneurobio.2007.10.011 · 9.99 Impact Factor
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