Uddin Mohammad Khaja Mafij, Kimura Wataru, Ishikura Tomoyuki, Koseki Haruhiko, Yoshida Nobuaki, Islam Mohammad Johirul, Amin Mohammed Badrul, Nakamura Kasumi, Wu Yi-Xin, Sato Eiji, Aoto Kazushi, Miura Naoyuki
Department of Biochemistry, Hamamatsu University School of Medicine.
Biomed Res. 2015;36(4):235-45. doi: 10.2220/biomedres.36.235.
The forkhead box C2 (Foxc2) protein is a member of the forkhead/winged helix transcription factor family and plays an essential role in cardiovascular development. Previous studies showed that Foxc2 null mouse embryos die during midgestation or just after birth with severe cardiovascular defects, including interruption, coarctation of the aortic arch and ventricular septal defects. These are also seen in human congenital heart disease. However, the tissue specific role of Foxc2 in aortic arch remodelling is not yet fully understood. Here we show that Foxc2 is expressed in a restricted pattern in several cell populations, including the mesenchyme and endothelium of pharyngeal arch arteries, which are important for cardiovascular development. In this study, we use a conditional knockout approach to examine the tissue specific role of Foxc2 in aortic arch remodelling. We demonstrate that mouse embryos lacking Foxc2 in Nkx2.5-expressing mesenchyme and endothelium of pharyngeal arch arteries display aortic arch interruption type B and ventricular septal defects. In contrast, conditional deletion of Foxc2 in Tie2-expressing endothelial cells does not result in aortic arch or ventricular septal defects, but does result in embryonic lethality due to peripheral oedema. Our data therefore provide for a detailed understanding of the role of mesenchymal Foxc2 in aortic arch remodelling and in the development of ventricular septum.
叉头框C2（Foxc2）蛋白是叉头/翼状螺旋转录因子家族的成员，在心血管发育中起重要作用。先前的研究表明，Foxc2基因敲除的小鼠胚胎在妊娠中期或出生后不久死亡，伴有严重的心血管缺陷，包括主动脉弓中断、缩窄和室间隔缺损。这些情况在人类先天性心脏病中也可见到。然而，Foxc2在主动脉弓重塑中的组织特异性作用尚未完全了解。在这里，我们表明Foxc2在几个细胞群体中以受限模式表达，包括对心血管发育很重要的咽弓动脉的间充质和内皮。在本研究中，我们使用条件性基因敲除方法来研究Foxc2在主动脉弓重塑中的组织特异性作用。我们证明，在咽弓动脉表达Nkx2.5的间充质和内皮中缺乏Foxc2的小鼠胚胎表现出B型主动脉弓中断和室间隔缺损。相比之下，在表达Tie2的内皮细胞中条件性删除Foxc2不会导致主动脉弓或室间隔缺损，但会因外周水肿导致胚胎致死。因此，我们的数据为详细了解间充质Foxc2在主动脉弓重塑和室间隔发育中的作用提供了依据。
