Characterization of new bone morphogenetic protein (Bmp)-2 regulatory alleles.
Characterization of new bone morphogenetic protein (Bmp)-2 regulatory alleles.
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DOI：
10.1002/dvg.23035
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Rogers MB
中科院分区：
文献类型：
--
作者：
Shah TA;Zhu Y;Shaikh NN;Harris MA;Harris SE;Rogers MB
骨形态发生蛋白2（BMP 2，HGNC：1069，GeneID：650）是一种经典的形态发生素;一种远距离作用的分子，其浓度影响细胞增殖，分化和凋亡。需要精确Bmp 2调节的关键事件包括心脏特化和形态发生以及神经发育。在间充质细胞中，BMP 2的浓度影响肌生成、脂肪生成、软骨生成和骨生成。由于BMP 2合成的数量、时间和位置影响模式形成和器官形成，因此调节BMP 2的机制至关重要。自鱼类和哺乳动物分化以来，Bmp 2 mRNA的3′UTR内的序列被称为“超保守序列”（UCS），在很大程度上没有改变。Cre-lox介导的报告基因中UCS的缺失揭示了UCS可以抑制心外膜、心外膜和心外膜衍生细胞（EPDC）和具有已知心外膜贡献的组织（冠状血管和瓣膜）中的Bmp 2。UCS还抑制了主动脉、出口隔、心脏后丛、心脏和心外神经以及神经节中的转基因。我们使用同源重组和条件性缺失来产生三个新的等位基因，其中Bmp 2 3′UTR被改变如下：UCS侧翼为loxP位点，有或没有新霉素抗性靶向载体，或缺失的UCS。UCS的缺失与Bmp 2 mRNA和BMP信号水平升高、适应性降低和胚胎畸形相关。
Bone morphogenetic protein 2 (BMP2, HGNC:1069, GeneID: 650) is a classical morphogen; a molecule that acts at a distance and whose concentration influences cell proliferation, differentiation, and apoptosis. Key events requiring precise Bmp2 regulation include heart specification and morphogenesis and neural development. In mesenchymal cells, the concentration of BMP2 influences myogenesis, adipogenesis, chondrogenesis, and osteogenesis. Because the amount, timing, and location of BMP2 synthesis influence pattern formation and organogenesis, the mechanisms that regulate Bmp2 are crucial. A sequence within the 3′UTR of the Bmp2 mRNA termed the “ultra-conserved sequence” (UCS) has been largely unchanged since fishes and mammals diverged. Cre-lox mediated deletion of the UCS in a reporter transgene revealed that the UCS may repress Bmp2 in proepicardium, epicardium and epicardium-derived cells (EPDC) and in tissues with known epicardial contributions (coronary vessels and valves). The UCS also repressed the transgene in the aorta, outlet septum, posterior cardiac plexus, cardiac and extra-cardiac nerves and neural ganglia. We used homologous recombination and conditional deletion to generate three new alleles in which the Bmp2 3′UTR was altered as follows: a UCS flanked by loxP sites with or without a neomycin resistance targeting vector, or a deleted UCS. Deletion of the UCS was associated with elevated Bmp2 mRNA and BMP signaling levels, reduced fitness, and embryonic malformations.
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