Epithelial differentiation and morphogenesis are fundamental to development and normal physiology. Their deregulation can cause cancer. During peri-implantation embryogenesis, the pluripotent inner cell mass of the blastocyst is converted from a nonpolar cell aggregate to a highly organized epithelial cyst. This morphogenetic transformation involves the formation of the polarized epiblast epithelium and apoptosis-mediated removal of the core cells. Despite the fundamental importance of these processes, both to development and to epithelial biology, there is limited understanding of the molecular mechanisms underlying these events. Thus, our long-term goal is to identify the extracellular cues and intracellular pathways that regulate epiblast differentiation, polarity and cavitation.
We use a unique experimental model system, the embryonic stem (ES) cell-derived embryoid body, which is a tissue structurally similar to the peri-implantation embryo. The embryoid body is amenable to biochemical and genetic manipulations and is a powerful tool with which to analyze the cellular and molecular events underlying epithelial morphogenesis. Using the embryoid body model system, we have uncovered novel interactions among the tumor suppressor PTEN, Rho GTPases and chromatin remodelers. We are studying how their interplay regulates ES cell differentiation and epithelial morphogenesis and how their deregulation causes malignant transformation.
We are also interested in the regulation of vascular network assembly from pluripotent stem cells. We have demonstrated an essential role for Cdc42 signaling in embryonic vasculogenesis. Our goal is to elucidate the upstream activators and downstream effectors of Cdc42 and use this knowledge to design rationally guided stem cell therapies.