Cre-mediated excision of Fgf8 in the Tbx1 expression domain reveals a critical role for Fgf8 in cardiovascular development in the mouse
Cre-mediated excision of Fgf8 in the Tbx1 expression domain reveals a critical role for Fgf8 in cardiovascular development in the mouse
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DOI：
10.1016/j.ydbio.2003.10.024
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发表时间：
2004-03-01
影响因子：
2.7
通讯作者：
Epstein, JA
中科院分区：
文献类型：
--
作者：
Brown, CB;Wenning, JM;Epstein, JA
Tbx1被认为是导致迪乔治/心面综合征中咽弓重塑缺陷的候选基因。Tbx1（+/-）小鼠以不同的外显率模拟迪乔治表型的某些方面，而基因敲除小鼠则表现出严重的咽部发育不全。在此，我们鉴定了Tbx1基因中在进化过程中保守且介导组织特异性表达的增强子元件。我们描述了利用这些增强子元件引导Cre重组酶在内源性Tbx1表达区域表达的转基因小鼠的产生过程。我们使用这些Tbx1 - Cre小鼠对表达Tbx1的前体细胞进行命运图谱分析，并确定了中胚层的广泛区域，包括早期心脏中胚层，它们都来源于表达Tbx1的细胞。我们通过使用Tbx1 - Cre小鼠对Fgf8进行组织特异性失活来验证成纤维细胞生长因子8（Fgf8）在Tbx1下游发挥作用这一假设。由此产生的新生小鼠表现出类似迪乔治的先天性心血管缺陷，涉及心脏流出道。大血管中的血管平滑肌分化被破坏。这些数据与一个模型相符，即Tbx1诱导咽内胚层中Fgf8的表达，而Fgf8随后对正常心血管形态发生以及主动脉和肺动脉中的平滑肌分化是必需的。（C）2003年爱思唯尔公司。保留所有权利。
Tbx1 has been implicated as a candidate gene responsible for defective pharyngeal arch remodeling in DiGeorge/Velocardiofacial syndrome. Tbx1(+/-) mice mimic aspects of the DiGeorge phenotype with variable penetrance, and null mice display severe pharyngeal hypoplasia. Here, we identify enhancer elements in the Tbx1 gene that are conserved through evolution and mediate tissue-specific expression. We describe the generation of transgenic mice that utilize these enhancer elements to direct Cre recombinase expression in endogenous Tbx1 expression domains. We use these Tbx1-Cre mice to fate map Tbx1-expressing precursors and identify broad regions of mesoderm, including early cardiac mesoderm, which are derived from Tbx1-expressing cells. We test the hypothesis that fibroblast growth factor 8 (Fgf8) functions downstream of Tbx1 by performing tissue-specific inactivation of Fgf8 using Tbx1-Cre mice. Resulting newborn mice display DiGeorge-like congenital cardiovascular defects that involve the outflow tract of the heart. Vascular smooth muscle differentiation in the great vessels is disrupted. This data is consistent with a model in which Tbx1 induces Fgf8 expression in the pharyngeal endoderm, which is subsequently required for normal cardiovascular morphogenesis and smooth muscle differentiation in the aorta and pulmonary artery. (C) 2003 Elsevier Inc. All rights reserved.