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タイトル: Functional Investigation of a Non-coding Variant Associated with Adolescent Idiopathic Scoliosis in Zebrafish: Elevated Expression of the Ladybird Homeobox Gene Causes Body Axis Deformation.
著者: Guo, Long
Yamashita, Hiroshi
Kou, Ikuyo
Takimoto, Aki
Meguro-Horike, Makiko
Horike, Shin-Ichi
Sakuma, Tetsushi  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0003-0396-1563 (unconfirmed)
Miura, Shigenori  KAKEN_id  orcid https://orcid.org/0000-0001-9206-2986 (unconfirmed)
Adachi, Taiji  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0001-5280-4156 (unconfirmed)
Yamamoto, Takashi
Ikegawa, Shiro
Hiraki, Yuji
Shukunami, Chisa
著者名の別形: 郭, 龍
山下, 寛
黄, 郁代
滝本, 晶
目黒-堀家, 牧子
堀家, 慎一
佐久間, 哲史
三浦, 重徳
安達, 泰治
山本, 卓
池川, 志郎
開, 祐司
宿南, 知佐
発行日: 28-Jan-2016
出版者: Public Library of Science
誌名: PLoS genetics
巻: 12
号: 1
論文番号: e1005802
抄録: Previously, we identified an adolescent idiopathic scoliosis susceptibility locus near human ladybird homeobox 1 (LBX1) and FLJ41350 by a genome-wide association study. Here, we characterized the associated non-coding variant and investigated the function of these genes. A chromosome conformation capture assay revealed that the genome region with the most significantly associated single nucleotide polymorphism (rs11190870) physically interacted with the promoter region of LBX1-FLJ41350. The promoter in the direction of LBX1, combined with a 590-bp region including rs11190870, had higher transcriptional activity with the risk allele than that with the non-risk allele in HEK 293T cells. The ubiquitous overexpression of human LBX1 or either of the zebrafish lbx genes (lbx1a, lbx1b, and lbx2), but not FLJ41350, in zebrafish embryos caused body curvature followed by death prior to vertebral column formation. Such body axis deformation was not observed in transcription activator-like effector nucleases mediated knockout zebrafish of lbx1b or lbx2. Mosaic expression of lbx1b driven by the GATA2 minimal promoter and the lbx1b enhancer in zebrafish significantly alleviated the embryonic lethal phenotype to allow observation of the later onset of the spinal curvature with or without vertebral malformation. Deformation of the embryonic body axis by lbx1b overexpression was associated with defects in convergent extension, which is a component of the main axis-elongation machinery in gastrulating embryos. In embryos overexpressing lbx1b, wnt5b, a ligand of the non-canonical Wnt/planar cell polarity (PCP) pathway, was significantly downregulated. Injection of mRNA for wnt5b or RhoA, a key downstream effector of Wnt/PCP signaling, rescued the defective convergent extension phenotype and attenuated the lbx1b-induced curvature of the body axis. Thus, our study presents a novel pathological feature of LBX1 and its zebrafish homologs in body axis deformation at various stages of embryonic and subsequent growth in zebrafish.
記述: 思春期特発性側弯症(AIS)の原因遺伝子LBX1が側弯を引き起こす仕組みを解明 --AIS治療法の確立へ期待--. 京都大学プレスリリース. 2016-02-01.
著作権等: © 2016 Guo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
URI: http://hdl.handle.net/2433/203649
DOI(出版社版): 10.1371/journal.pgen.1005802
PubMed ID: 26820155
関連リンク: http://www.kyoto-u.ac.jp/ja/research/research_results/2015/160129_1.html
出現コレクション:学術雑誌掲載論文等

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