MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, China.
Dev Biol. 2010 Nov 15;347(2):384-91. doi: 10.1016/j.ydbio.2010.08.033. Epub 2010 Sep 15.
The PI3K-PDK1-PKB/Akt (PI3K, phosphoinositide-3 kinase; PDK1, phosphoinositide-dependent protein kinase 1; PKB, protein kinase B) signaling pathway plays a critical role in a variety of biological processes including cell survival, growth and proliferation, metabolism and organogenesis. Previously, we generated Akt1-deficient mice and found high neonatal mortality with unknown causes. Here we report that histological analysis of Akt1-deficient embryos and newborns revealed heart defects and decreased cell proliferation. Echocardiographic study of Akt1-deficient mice indicated decreased heart function. Further investigation revealed that Akt1 deficiency caused substantial activation of p38MAPK in the heart. Breeding the Akt1-deficient mice to mice that were heterozygous for a null p38α partially rescued the heart defects, significantly decreased post-natal mortality, and restored normal patterns of cardiomyocyte proliferation. Our study suggests that Akt1 is essential for heart development and function, in part, through suppression of p38MAPK activation.
PI3K-PDK1-PKB/Akt（PI3K，磷酸肌醇-3 激酶；PDK1，磷酸肌醇依赖性蛋白激酶 1；PKB，蛋白激酶 B）信号通路在多种生物过程中发挥着关键作用，包括细胞存活、生长和增殖、代谢和器官发生。此前，我们生成了 Akt1 缺陷型小鼠，并发现其具有不明原因的高新生儿死亡率。在这里，我们报告称 Akt1 缺陷型胚胎和新生儿的组织学分析显示存在心脏缺陷和细胞增殖减少。Akt1 缺陷型小鼠的超声心动图研究表明心脏功能下降。进一步的研究表明，Akt1 缺陷导致心脏中 p38MAPK 的大量激活。将 Akt1 缺陷型小鼠与 p38α 杂合缺失的小鼠进行杂交，部分挽救了心脏缺陷，显著降低了出生后死亡率，并恢复了正常的心肌细胞增殖模式。我们的研究表明，Akt1 通过抑制 p38MAPK 的激活，对心脏发育和功能至关重要。
