Ma Mancheong, Li Peng, Shen Hua, Estrada Kristine D, Xu Jian, Kumar S Ram, Sucov Henry M
Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, USA.
Dev Biol. 2016 Jan 1;409(1):272-276. doi: 10.1016/j.ydbio.2015.09.021. Epub 2015 Oct 29.
Heart outflow tract septation in mouse embryos carrying mutations in retinoic acid receptor genes fails with complete penetrance. In this mutant background, ectopic TGFβ signaling in the distal outflow tract is responsible for septation failure, but it was uncertain what tissue was responsive to ectopic TGFβ and why this response interfered with septation. By combining RAR gene mutation with tissue-specific Cre drivers and a conditional type II TGFβ receptor (Tgfbr2) allele, we determined that ectopic activation of TGFβ signaling in the endocardium is responsible for septation defects. Ectopic TGFβ signaling results in ectopic mesenchymal transformation of the endocardium and thereby in improperly constituted distal OFT cushions. Our analysis highlights the interactions between myocardium, endocardium, and neural crest cells in outflow tract morphogenesis, and demonstrates the requirement for proper TGFβ signaling in outflow tract cushion organization and septation.
在视黄酸受体基因发生突变的小鼠胚胎中，心脏流出道分隔完全失效。在这种突变背景下，远端流出道中异位的TGFβ信号传导是分隔失败的原因，但尚不清楚哪种组织对异位TGFβ有反应以及这种反应为何会干扰分隔。通过将RAR基因突变与组织特异性Cre驱动因子和条件性II型TGFβ受体（Tgfbr2）等位基因相结合，我们确定心内膜中TGFβ信号的异位激活是分隔缺陷的原因。异位TGFβ信号传导导致心内膜的异位间充质转化，从而导致远端OFT垫构成不当。我们的分析突出了心肌、心内膜和神经嵴细胞在流出道形态发生中的相互作用，并证明了在流出道垫组织和分隔中适当的TGFβ信号传导的必要性。
