Liu Wei, Selever Jennifer, Wang Degang, Lu Mei-Fang, Moses Kelvin A, Schwartz Robert J, Martin James F
Alkek Institute of Biosciences and Technology, Texas A&M University System Health Science Center, 2121 Holcombe Boulevard, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4489-94. doi: 10.1073/pnas.0308466101. Epub 2004 Mar 19.
The Bmp4 signaling molecule is expressed in ventral splanchnic and branchial-arch mesoderm and outflow-tract (OFT) myocardium, suggesting a role for Bmp4 in OFT development. Inactivation of Bmp4 in the caudal branchial arch and splanchnic mesoderm and OFT myocardium by using a conditional null allele of Bmp4 and the Nkx2.5cre recombinase allele resulted in abnormal morphogenesis of branchial-arch arteries (BAAs) and defective OFT septation. Expression of aortic-sac myocardial markers was reduced and expression of the sm22LacZ transgene, a smooth-muscle marker, was attenuated in BAAs and conotruncus of Nkx2.5cre; Bmp4 conditional mutants. Moreover, we found tissue-specific functions for Bmp4 in the regulation of cellular proliferation and apoptosis. We also demonstrate a strong genetic interaction between Bmp4 and Bmp7 in OFT development. Our findings uncover a previously uncharacterized function for Bmp4 in vascular remodeling of the BAAs, and they show definitively that Bmp4, in cooperation with Bmp7, has a central role in OFT septation.
Bmp4信号分子在腹侧脏壁和鳃弓中胚层以及流出道（OFT）心肌中表达，提示Bmp4在OFT发育中发挥作用。利用Bmp4的条件性无效等位基因和Nkx2.5cre重组酶等位基因使尾侧鳃弓、脏壁中胚层和OFT心肌中的Bmp4失活，导致鳃弓动脉（BAA）形态发生异常和OFT分隔缺陷。在Nkx2.5cre；Bmp4条件性突变体的BAA和圆锥干中，主动脉囊心肌标志物的表达降低，平滑肌标志物sm22LacZ转基因的表达减弱。此外，我们发现Bmp4在细胞增殖和凋亡调控中具有组织特异性功能。我们还证明了Bmp4和Bmp7在OFT发育中存在强烈的遗传相互作用。我们的研究结果揭示了Bmp4在BAA血管重塑中以前未被描述的功能，并且明确表明Bmp4与Bmp7协同作用在OFT分隔中起核心作用。
