sonic hedgehog is required in pulmonary endoderm for atrial septation
sonic hedgehog is required in pulmonary endoderm for atrial septation
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DOI：
10.1242/dev.034157
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发表时间：
2009-05-15
期刊：
影响因子：
4.6
通讯作者：
Moskowitz, Ivan P.
中科院分区：
文献类型：
--
作者：
Hoffmann, Andrew D.;Peterson, Michael A.;Moskowitz, Ivan P.
哺乳动物心脏间隔结构的发生是理解先天性心脏病个体发生和心脏器官发生进化的核心。我们发现Hedgehog（Hh）信号标记了小鼠房间隔和肺动脉干特异性心脏祖细胞的一个子集。使用Gli 1（CreERT 2）的遗传诱导命运映射，我们标记了E8和E10之间的前部和后部第二心脏区域内脏中胚层中的Hh接收祖细胞。在流入道中，Hh-接收祖细胞从后第二心野通过背侧间充质膜迁移形成房间隔，包括初级房间隔和背侧间充质突起（dorsal mesenchymal protrusion，EEP）。在流出道中，Hh-接收祖细胞从前第二心脏区域迁移到肺动脉干。房间隔祖细胞特化过程中Hh信号的消除导致心房和房室间隔缺损以及发育中的心房发育不全。Hedgehog信号似乎是房间隔祖细胞命运的必要和充分条件：Hh受体细胞对Hh配体无反应，以正常数量迁移到心房，但聚集在心房游离壁而不是房间隔。相反，Hh信号的组成性激活导致房间隔不适当的扩大。后第二心脏领域的心脏祖细胞的肺内胚层的紧密接近建议肺源的Hh配体。我们发现，肺内胚层的心房分隔需要Shh。因此，来自不同的肺和咽内胚层的Hh信号传导分别是流入和流出分隔所需的。这些数据表明，呼吸内胚层模式的有效心肺循环所需的心脏结构组件的形态发生的模型。
The genesis of the septal structures of the mammalian heart is central to understanding the ontogeny of congenital heart disease and the evolution of cardiac organogenesis. We found that Hedgehog (Hh) signaling marked a subset of cardiac progenitors specific to the atrial septum and the pulmonary trunk in the mouse. Using genetic inducible fate mapping with Gli1(CreERT2), we marked Hh-receiving progenitors in anterior and posterior second heart field splanchnic mesoderm between E8 and E10. In the inflow tract, Hh-receiving progenitors migrated from the posterior second heart field through the dorsal mesocardium to form the atrial septum, including both the primary atrial septum and dorsal mesenchymal protrusion (DMP). In the outflow tract, Hh-receiving progenitors migrated from the anterior second heart field to populate the pulmonary trunk. Abrogation of Hh signaling during atrial septal progenitor specification resulted in atrial and atrioventricular septal defects and hypoplasia of the developing DMP. Hedgehog signaling appeared necessary and sufficient for atrial septal progenitor fate: Hh-receiving cells rendered unresponsive to the Hh ligand migrated into the atrium in normal numbers but populated the atrial free wall rather than the atrial septum. Conversely, constitutive activation of Hh signaling caused inappropriate enlargement of the atrial septum. The close proximity of posterior second heart field cardiac progenitors to pulmonary endoderm suggested a pulmonary source for the Hh ligand. We found that Shh is required in the pulmonary endoderm for atrial septation. Therefore, Hh signaling from distinct pulmonary and pharyngeal endoderm is required for inflow and outflow septation, respectively. These data suggest a model in which respiratory endoderm patterns the morphogenesis of cardiac structural components required for efficient cardiopulmonary circulation.