Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim, Germany.
German Centre for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Bad Nauheim, Germany.
Nat Commun. 2023 Jan 13;14(1):214. doi: 10.1038/s41467-023-35843-3.
Cardiac valves ensure unidirectional blood flow through the heart, and altering their function can result in heart failure. Flow sensing via wall shear stress and wall stretching through the action of mechanosensors can modulate cardiac valve formation. However, the identity and precise role of the key mechanosensors and their effectors remain mostly unknown. Here, we genetically dissect the role of Pkd1a and other mechanosensors in atrioventricular (AV) valve formation in zebrafish and identify a role for several pkd and piezo gene family members in this process. We show that Pkd1a, together with Pkd2, Pkd1l1, and Piezo2a, promotes AV valve elongation and cardiac morphogenesis. Mechanistically, Pkd1a, Pkd2, and Pkd1l1 all repress the expression of klf2a and klf2b, transcription factor genes implicated in AV valve development. Furthermore, we find that the calcium-dependent protein kinase Camk2g is required downstream of Pkd function to repress klf2a expression. Altogether, these data identify, and dissect the role of, several mechanosensors required for AV valve formation, thereby broadening our understanding of cardiac valvulogenesis.
心脏瓣膜确保血液单向流过心脏，改变它们的功能可能导致心力衰竭。通过壁切应力和机械感受器的作用对壁拉伸进行流量感应，可以调节心脏瓣膜的形成。然而，关键机械感受器及其效应器的确切身份和作用仍知之甚少。在这里，我们通过遗传方法在斑马鱼中剖析了 Pkd1a 和其他机械感受器在房室（AV）瓣膜形成中的作用，并确定了几个 pkd 和 piezo 基因家族成员在该过程中的作用。我们表明，Pkd1a 与 Pkd2、Pkd1l1 和 Piezo2a 一起促进 AV 瓣膜伸长和心脏形态发生。在机制上，Pkd1a、Pkd2 和 Pkd1l1 均抑制 klf2a 和 klf2b 的表达，klf2a 和 klf2b 是参与 AV 瓣膜发育的转录因子基因。此外，我们发现钙依赖性蛋白激酶 Camk2g 是 Pkd 功能下游抑制 klf2a 表达所必需的。总之，这些数据确定并剖析了几个机械感受器在 AV 瓣膜形成中的作用，从而拓宽了我们对心脏瓣膜发生的理解。
