Department of Physiology and Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea.
Department of Life Science, Ewha Womans University, Seoul, Republic of Korea.
PLoS One. 2021 Oct 29;16(10):e0259426. doi: 10.1371/journal.pone.0259426. eCollection 2021.
ERBB family members and their ligands play an essential role in embryonic heart development and adult heart physiology. Among them, ERBB3 is a binding partner of ERBB2; the ERBB2/3 complex mediates downstream signaling for cell proliferation. ERBB3 has seven consensus binding sites to the p85 regulatory subunit of PI3K, which activates the downstream AKT pathway, leading to the proliferation of various cells. This study generated a human ERBB3 knock-in mouse expressing a mutant ERBB3 whose seven YXXM p85 binding sites were replaced with YXXA. Erbb3 knock-in embryos exhibited lethality between E12.5 to E13.5, and showed a decrease in mesenchymal cell numbers and density in AV cushions. We determined that the proliferation of mesenchymal cells in the atrioventricular (AV) cushion in Erbb3 knock-in mutant embryos was temporarily reduced due to the decrease of AKT and ERK1/2 phosphorylation. Overall, our results suggest that AKT/ERK activation by the ERBB3-dependent PI3K signaling is crucial for AV cushion morphogenesis during embryonic heart development.
ERBB 家族成员及其配体在胚胎心脏发育和成人心脏生理学中发挥着重要作用。其中，ERBB3 是 ERBB2 的结合伴侣；ERBB2/3 复合物介导细胞增殖的下游信号转导。ERBB3 有七个与 PI3K 调节亚基 p85 的共识结合位点，可激活下游 AKT 通路，导致各种细胞的增殖。本研究构建了一种表达突变型 ERBB3 的人 ERBB3 敲入小鼠，其七个 YXXM p85 结合位点被替换为 YXXA。Erbb3 敲入胚胎在 E12.5 至 E13.5 之间表现出致死性，并显示房室（AV）间隔垫中的间充质细胞数量和密度减少。我们确定，由于 AKT 和 ERK1/2 磷酸化的减少，AV 间隔垫中间充质细胞的增殖在 Erbb3 敲入突变胚胎中暂时减少。总体而言，我们的结果表明，ERBB3 依赖性 PI3K 信号转导的 AKT/ERK 激活对于胚胎心脏发育过程中 AV 间隔垫形态发生至关重要。
