Signaling and epigenetic control of stem/progenitor development

Although much is known about the anterior portion of the developing heart, little is understood about the development of the posterior portion or inflow tract region. Wnt/beta‐catenin signaling has been shown to play an important role in regulating expansion and differentiation of second heart field (SHF) progenitors. These studies have used both gain and loss of function models in the critical signaling regulator beta‐catenin. However, beta‐catenin plays various roles in the cell outside of Wnt signaling including regulation of cell‐cell interactions. We have explored the role of Wnt signaling using loss of function studies for important Wnt ligands and receptors. Our studies show that Wnt2, which is expressed specifically in the posterior portion of the cardiac inflow tract region, is essential for development of the atria and atrioventricular canal. Wnt acts through the beta‐catenin dependent canonical Wnt pathway and cooperates with the transcription factor Gata6 to regulate both proliferation and differentiation of posterior SHF progenitors. The defects in Wnt2 mutants can be rescued with a temporal restricted application of LiCl, a known Wnt/Gsk3beta agonist. We will also present data on regulation of SHF progenitors by Wnt5a and Wnt11. Together, our work provides a frame work to explore the self‐renewal and differentiation of early cardiac progenitors in vivo and ex vivo.