Nkx genes establish second heart field cardiomyocyte progenitors at the arterial pole and pattern the venous pole through Isl1 repression
Nkx genes establish second heart field cardiomyocyte progenitors at the arterial pole and pattern the venous pole through Isl1 repression
复制标题
DOI：
10.1242/dev.161497
复制
发表时间：
2018-02-01
期刊：
影响因子：
4.6
通讯作者：
Targoff, Kimara L.
中科院分区：
文献类型：
--
作者：
Colombo, Sophie;de Sena-Tomas, Carmen;Targoff, Kimara L.
Nkx2-5是与人类先天性心脏病(CHDS)相关的最常见的突变基因，易发生心极异常。这种同源结构域转录因子是心脏发育的中央调节因子，在第一和第二心脏区域(FHF和SHF)都有表达。我们之前已经揭示了在斑马鱼心肌细胞中表达的两个Nkx2-5同源物NKX2.5和Nkx2.7在维持心室特性方面的重要功能。然而，这些基因在前(ASHF)和后(PSHF)SHF特定亚群中的不同作用尚未完全确定。在这里，我们发现Nkx基因通过独立的机制调节aSHF和pSHF前体细胞。我们证明了Nkx基因限制了流出道中aSHF前体细胞的增殖，限定了静脉端pSHF前体细胞的数量，并通过Isl1抑制作用形成了窦房结。此外，光学作图强调了Nkx基因剂量在建立电生理室特性以及整合FHF和SHF心肌细胞的生理连接方面的需求。最终，我们的结果可能有助于揭示导致NKX2-5依赖的人类CHD的心脏流出和流入道的离散错误。
NKX2-5 is the most commonly mutated gene associated with human congenital heart defects (CHDs), with a predilection for cardiac pole abnormalities. This homeodomain transcription factor is a central regulator of cardiac development and is expressed in both the first and second heart fields (FHF and SHF). We have previously revealed essential functions of nkx2.5 and nkx2.7, two Nkx2-5 homologs expressed in zebrafish cardiomyocytes, in maintaining ventricular identity. However, the differential roles of these genes in the specific subpopulations of the anterior (aSHF) and posterior (pSHF) SHFs have yet to be fully defined. Here, we show that Nkx genes regulate aSHF and pSHF progenitors through independent mechanisms. We demonstrate that Nkx genes restrict proliferation of aSHF progenitors in the outflow tract, delimit the number of pSHF progenitors at the venous pole and pattern the sinoatrial node acting through Isl1 repression. Moreover, optical mapping highlights the requirement for Nkx gene dose in establishing electrophysiological chamber identity and in integrating the physiological connectivity of FHF and SHF cardiomyocytes. Ultimately, our results may shed light on the discrete errors responsible for NKX2-5-dependent human CHDs of the cardiac outflow and inflow tracts.