Identification of transcriptional regulatory elements for Ntng1 and Ntng2 genes in mice

abstract: ...Background 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. Results 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 8545kb upstream region of Ntng2 and in the 7560kb 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. Conclusions 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.

...Mol Brain Mol Brain Molecular Brain 1756-6606 BioMed Central 24642214 4000137 1756-6606-7-19 10.1186/1756-6606-7-19 Research Identification of transcriptional regulatory elements for Ntng1 and Ntng2 genes in mice Yaguchi Kunio 1 2 yaguchi@brain.riken.jp Nishimura-Akiyoshi Sachiko 1 Sachiko.Akiyoshi@biophys.mpg.de Kuroki Satoshi 1 s.kuroki@brain.riken.jp Onodera Takashi 2 aonoder@mail.ecc.u-tokyo.ac.jp Itohara Shigeyoshi 1 sitohara@brain.riken.jp 1 RIKEN Brain Science Institute, 2-1 Hirosawa

..., provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated. Background 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

... that major cis -regulatory elements are located in the 8545kb upstream region of Ntng2 and in the 7560kb 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. Conclusions 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

... identification of sequences that control the location and timing of gene expression in the brain is a crucial challenge in neuroscience. Netrin-G1 ( Ntng1 ) and netrin-G2 ( Ntng2) , also called laminet 1 and laminet 2, respectively, are UNC-6/netrin family members [ 4 - 6 ]. Classic netrins are phylogenetically conserved diffusible chemoattractants of axon guidance molecules [ 7 - 9 ]. Unlike classic netrins, netrin-Gs are linked to the plasma membrane surface by a glycosyl-phosphatidylinositol linkage, have no invertebrate orthologs, and lack affinity to the known netrin receptor families [ 4 , 5 ]. Netrin-G1 and netrin-G2 interact with specific receptors. Netrin-G1 interacts with netrin-G1 ligand (NGL1) [ 10 ], whereas netrin-G2 interacts with NGL2 [ 11 , 12 ]. 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 ]. NTNG1 and NTNG2 alterations might also be involved in bipolar disease [ 21 , 22 ]. Studies with netrin-G1 and netrin-G2 knock-out (KO) mice have revealed the crucial significance of their differential expression in higher brain functions [ 12 ]. Elucidation of the transcriptional mechanisms that regulate the complementary expression of Ntng1 and Ntng2 will help to clarify the mechanisms of vertebrate-specific neural circuit formation and function, and will act as a springboard for novel cutting-edge research designed to gain a better understanding of the basis of higher brain function in vertebrates. Mouse Ntng1 and Ntng2 are large genes that span more than 362kb and 53kb, respectively. Their cis -regulatory

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Gene: NTNG2 - netrin G2 - (NCBI)

Protein : 3zyg

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