Molecular cascades underlying the integration of cell differentiation and morphogenesis in cranial/cardiac neural crest development

颅/心脏神经嵴发育中细胞分化和形态发生整合的分子级联

• 批准号: 16390218
• 负责人: KURIHARA Hiroki
• 金额: $ 9.15万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390218/
• 关键词: Neural crest cells; Pharyngeal arch; Cardiovascular development; Embryo genesis; Endothelin; Homeotic genes; Calpain; Transcriptional factors; 細胞内シグナル; 心血管発生; 細胞分化; 形態形成; Dlx

1.We have found that endothelin-1, produced by pharyngeal epithelium and core mesoderm, acts on cranial neural crest cells via ET-A receptor (ETAR) and determines the ventral identity of the anterior pharyngeal arches by inducing homeotic genes Dlx5 and Dlx6. After the regional specification by ET-1, Dlx5/6 expression was proved to be maintained by the FGF signaling.2.We have found that the ET-1 signaling activates the enhancer activity of m5/6i, the intergenic element of the Dlx5/6loci, leading to the upregulation of Dlx5/6 expression.3.We have established mice expressing GFP under the ETAR gene promoter to visualize the ETAR-expressing cells. We also realized the transgenic mouse system in which any genes of interest can be efficiently knocked-in into the ETAR locus by Cre recombinase-mediated cassette exchange. Using this system, we could knock-in the lacZgene to definitely identify the ETAR-expressing cells.4.We have identified Capn6 as a gene downstream to the ET-1 signaling using DNA microarray. Capn6 was found to be possibly involved in cell division and morphology through the regulation of microtubular networks.5.We have identified TAZ, a transcriptional coactivator, as a Pax3-binding protein. TAZ was found to coactivate the transcriptional activity of Pax3. TAZ-lacZ knock-in mice have identified TAZ expressing cells during embryogenesis. Partial lethality of TAZ-lacZ knock-in mice has indicated the importance of this gene in development.

1.我们发现，由咽上皮和核心中胚层产生的内皮素-1通过ET-A受体(ETAR)作用于颅神经脊细胞，并通过诱导同源基因D1x5和Dlx6决定咽前弓的腹侧特性。经ET-1的区域定位后，Dlx5/6的表达由成纤维细胞生长因子信号维持。2.我们发现ET-1信号激活了Dlx5/6基因座的间隔区元件M5/6i的增强子活性，导致Dlx5/6的表达上调。3.我们建立了在Etar基因启动子下表达GFP的小鼠，以可视化表达Etar的细胞。我们还实现了转基因小鼠系统，在该系统中，任何感兴趣的基因都可以通过Cre重组酶介导盒交换有效地插入Etar基因座。利用这个系统，我们可以通过敲入lacZ基因来明确鉴定表达Etar的细胞。4.我们利用DNA芯片鉴定了Capn6是ET-1信号转导下游的一个基因。Capn6可能通过调节微管网络参与细胞的分裂和形态。5.我们鉴定了转录共激活因子TAZ是一种Pax3结合蛋白。TAZ被发现共激活了Pax3的转录活性。Taz-LacZ敲入小鼠已发现在胚胎发育过程中表达TAZ的细胞。TAZ-LacZ基因敲除小鼠的部分致死率表明了该基因在发育过程中的重要性。

项目成果

Transcriptional activity of Pax3 is co-activated by TAZ

• DOI: 10.1016/j.bbrc.2005.10.214
• 发表时间: 2006-01-13
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Murakami, M;Tominaga, J;Kurihara, H
• 通讯作者: Kurihara, H

Fluvastatin ameliorates the hyperhomocysteinemia-induced endothelial dysfunction - The antioxidative properties of fluvastatin

• DOI: 10.1253/circj.69.475
• 发表时间: 2005-04-01
• 期刊: CIRCULATION JOURNAL
• 影响因子: 3.3
• 作者: Morita, H;Saito, Y;Nagai, R
• 通讯作者: Nagai, R

Resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet.

抵抗素样分子β激活MAPK，抑制肝细胞中的胰岛素信号传导，并在高脂肪饮食的转基因小鼠中诱发糖尿病、高脂血症和脂肪肝。

• 发表时间: 2005
• 期刊: J.Biol.Chem. 280・51
• 作者: Viana AY;Sakoda H;et al.;Kushiyama A et al.
• 通讯作者: Kushiyama A et al.

Overexpression of lectin-line oxidized low-density lipoprotein receptor-1 induces intramyocardial vasculopathy in apolipoprotein E-null mice.

凝集素线氧化低密度脂蛋白受体 1 的过度表达可诱导载脂蛋白 E 缺失小鼠发生心肌内血管病变。

• 发表时间: 2005
• 期刊: Circ. Res. 97
• 作者: Kojima;S.;et. al.;Yokoyama Y;Inoue K
• 通讯作者: Inoue K

MADAMTS-1 is involved in normal follicular development, ovulatory process and organization of the medullary vascular network in the ovary.

MADAMTS-1 参与正常卵泡发育、排卵过程和卵巢髓质血管网络的组织。

• 发表时间: 2005
• 期刊: J.Mol.Endocrinol. 35
• 作者: Isomoto H;Ueno H;Saenko VA;Mondal MS;Nishi Y;Kawano N;Ohnita K;Mizuta Y;Ohtsuru A;Yamashita S;Nakazato M;Kohno S.;Yamamoto N;Shozu M
• 通讯作者: Shozu M