title: Akt1 signaling coordinates BMP signaling and β-catenin activity to regulate second heart field progenitor development.
abstract: Second heart field (SHF) progenitors exhibit continued proliferation and delayed differentiation, which are modulated by FGF4/8/10, BMP and canonical Wnt/β-catenin signaling. PTEN-Akt signaling regulates the stem cell/progenitor cell homeostasis in several systems, such as hematopoietic stem cells, intestinal stem cells and neural progenitor cells. To address whether PTEN-Akt signaling is involved in regulating cardiac progenitors, we deleted Pten in SHF progenitors. Deletion of Pten caused SHF expansion and increased the size of the SHF derivatives, the right ventricle and the outflow tract. Cell proliferation of cardiac progenitors was enhanced, whereas cardiac differentiation was unaffected by Pten deletion. Removal of Akt1 rescued the phenotype and early lethality of Pten deletion mice, suggesting that Akt1 was the key downstream target that was negatively regulated by PTEN in cardiac progenitors. Furthermore, we found that inhibition of FOXO by Akt1 suppressed the expression of the gene encoding the BMP ligand (BMP7), leading to dampened BMP signaling in the hearts of Pten deletion mice. Cardiac activation of Akt also increased the Ser552 phosphorylation of β-catenin, thus enhancing its activity. Reducing β-catenin levels could partially rescue heart defects of Pten deletion mice. We conclude that Akt signaling regulates the cell proliferation of SHF progenitors through coordination of BMP signaling and β-catenin activity.
authors: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China.
authors: Wen
authors: W
authors: Luo
authors: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China.
authors: Xia
authors: X
authors: Zhao
authors: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China.
authors: Hengwei
authors: H
authors: Jin
authors: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China.
authors: Lichan
authors: L
authors: Tao
authors: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China.
authors: Jingai
authors: J
authors: Zhu
authors: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China.
authors: Huijuan
authors: H
authors: Wang
authors: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors: Brian A
authors: BA
authors: Hemmings
authors: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, China Collaborative Innovation Center for Genetics and Development, Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai 200438, China zhongzhouyang@nju.edu.cn.
authors: Zhongzhou
authors: Z
authors: Yang
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D006321:Heart / Q000196:embryology*; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Akt; BMP; Mouse; Second heart field; β-catenin