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.

FGF10 Signaling in Heart Development, Homeostasis, Disease and Repair

“…Indeed, transgenic mouse models with conditional inactivation of Fgfr1/2 , conditional overexpression of Sprouty2 ( Spry2 , which encodes an FGF signaling antagonist) or conditional ablation of Frs2 (encoding a MAPK/PI3K signaling adaptor protein) within the SHF progenitor cell population revealed that interrupting autocrine FGF signaling in SHF mesoderm, by compromising SHF progenitor cell proliferation and by indirectly reducing cardiac neural crest cell recruitment into the outflow tract cushions, causes outflow tract misalignment and subsequently impaired cardiac morphogenesis ( Park et al, 2008 ; Zhang et al, 2008 ). While FGFR-dependent regulation of SHF proliferation seems to depend on the PI3K/AKT pathway ( Luo et al, 2015 ), the Ras/Erk downstream signaling seems to be required in the regulation of myocardial specification ( Rochais et al, 2009 ; Hutson et al, 2010 ). All these studies thus strongly reveal iterative roles for FGF signaling in OFT development.…”

The advancement of human pluripotent stem cell-derived therapies into the clinic

“…For this trial, the I6 hESC line is expanded on a feeder layer of clinical-grade human fibroblasts and differentiated using bone morphogenetic protein (BMP)-2 and the FGF receptor kinase inhibitor SU-5402 for 4 days (Menasché et al, 2014). BMP-2 and the closely related TGF-β superfamily member BMP-4 are important regulators of mesoderm formation and cardiogenesis (Winnier et al, 1995;Schultheiss et al, 1997;Song et al, 2014;Luo et al, 2015). Inhibition of FGF signaling was observed to improve the efficiency of cardiac differentiation mediated by BMP-2 (Tomescot et al, 2007).…”

HAND2-mediated epithelial maintenance and integrity in cardiac outflow tract morphogenesis

“…To understand the cause of cell accumulation in the distal OFT of Hand2 mutant mice, we examined cell proliferation and survival. Previous work showed that enhanced thymoma viral protooncogene 1 (Akt) signaling in aSHF progenitors promotes cell proliferation in the caudal SpM, the increased progenitor pool of which can be visualized directly by using a GFP reporter mouse line at E9.5 (Luo et al, 2015). Thus, we used this strategy to examine the progenitor pool in Hand2 mutant and control mice at E9.5.…”