Department of Anatomy and Developmental Biology, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Street 7-11, 68167 Mannheim, Germany; Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
Department of Anatomy and Developmental Biology, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Street 7-11, 68167 Mannheim, Germany; Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Mannheim, Germany.
Stem Cell Reports. 2021 Aug 10;16(8):1894-1905. doi: 10.1016/j.stemcr.2021.06.017. Epub 2021 Jul 29.
During development, cells respond rapidly to intra- and intercellular signals, which induce signaling cascades regulating the activity of transcription factors at the transcriptional and/or post-translational level. The transcription factor ISL1 plays a key role in second heart field development and cardiac differentiation, and its mRNA levels are tightly regulated during cardiogenesis. Here, we show that a BMP-p38 MAPK signaling axis controls ISL1 protein function at the post-translational level. BMP-mediated activation of p38 MAPK leads to ISL1 phosphorylation at S269 by p38, which prevents ISL1 degradation and ensures its transcriptional activity during cardiogenesis. Interfering with p38 MAPK signaling leads to the degradation of ISL1 by the proteasome, resulting in defects in cardiomyocyte differentiation and impaired zebrafish and mouse heart morphogenesis and function. Given the critical role of the tight control of ISL1 activity during cardiac lineage diversification, modulation of BMP4-p38 MAPK signaling could direct differentiation into specific cardiac cell subpopulations.
在发育过程中，细胞对细胞内和细胞间信号做出快速响应，这些信号诱导信号级联反应，在转录和/或翻译后水平调节转录因子的活性。转录因子 ISL1 在第二心脏场发育和心脏分化中发挥关键作用，其 mRNA 水平在心脏发生过程中受到严格调控。在这里，我们表明 BMP-p38 MAPK 信号轴在翻译后水平控制 ISL1 蛋白功能。BMP 介导的 p38 MAPK 激活导致 p38 对 ISL1 的 S269 进行磷酸化，从而防止 ISL1 降解，并确保其在心脏发生过程中的转录活性。干扰 p38 MAPK 信号会导致蛋白酶体降解 ISL1，导致心肌细胞分化缺陷，并损害斑马鱼和小鼠心脏形态发生和功能。鉴于 ISL1 活性在心脏谱系多样化过程中的严格控制的关键作用，BMP4-p38 MAPK 信号的调节可能会指导分化为特定的心脏细胞亚群。
