Primary AppointmentCell Biology
Jordan Hall - Room 3218
Charlottesville, VA 22903
Telephone: 434 243 6613
Molecular Mechanisms of Early Vertebrate Development and Morphogenesis. Application to Stem Cell Biology and Regenerative Medicine
Morphogenesis concerns the fundamental question of the biological form, including the study of how cellular differentiation and cell growth occur, leading to the formation of stereotypical and well shaped tissues and organs. Our lab investigates how a vertebrate embryo is patterned and gets its shape during early stages of embryogenesis. We use 2 model systems: the early zebrafish embryo and embryoid bodies made of mouse embryonic stem cells. During the past two decades, we have achieved an extensive analysis of the factors responsible for establishing the dorso-ventral and antero-posterior axes of the zebrafish embryo, focusing on the role of BMP, FGFs and their respective inhibitors (Furthauer et al, 2001; Furthauer et al, 2002; Furthauer et al, 2004) and of Nodal, Activin and their antagonist Antivin/Lefty (Thisse and Thisse, 1999; Thisse et al, 2000; Agathon et al, 2003). We identified also the maternally provided Wnt8a as the factor responsible for the first symmetry-breaking event in the embryo and defined how its activity is regulated by specific antagonists (Lu et al 2011). Part of the lab is now studying how Left-Right asymmetry is setup and controlled. We recently discovered an unsuspected role for factors mediating or regulating the transcriptional response to the Hippo pathway (known as a major regulator of tissue growth and organ size through the regulation of cell proliferation and apoptosis) in the formation of the ciliated organ responsible for the Left-Right asymmetry of the embryo: the Left-right organizer. Using Talen and Crispr/Cas9 editing technologies as well as various gain of function and gene knockdown methods, we are currently dissecting the molecular mechanisms regulating the formation of the Left-Right organizer. In addition, through a comprehensive analysis of the transcriptome of its precursor cells in various loss of function conditions, we will characterize the cascade of gene products involved in its formation and function. Development of vertebrate embryos involves tightly regulated molecular and cellular processes that progressively instruct proliferating embryonic cells about their identity and behavior. Looking for the minimal conditions and factors that are sufficient to instruct pluripotent cells to organize the embryo, we found that as little as two opposing gradients of morphogens, BMP and Nodal, are sufficient to induce molecular and cellular mechanisms required to organize uncommitted cells of the zebrafish blastula into a well-developed embryo. Applying this combination of two gradients is also sufficient to instruct pluripotent zebrafish blastula cells to organize, in vitro, embryoids containing a full range of tissues and organs (Fauny et al, 2009; Xu et al, 2014; Thisse and Thisse, 2015). Because the signaling pathways controlling the early embryonic development have been conserved across evolution, we predict that these findings can apply to the organization of early mammalian embryos. Therefore, we are now trying to take control of aggregates of mouse embryonic stem cells (embryoid bodies), instructing them through experimentally engineered morphogen gradients that should allow us to control cell fate and morphogenesis. Our goal is to use this approach to induce the formation of tissues and organs in vitro. We predict that this study will have a significant impact on Stem Cell Biology research and will move the field of Regenerative Medicine closer to the goal of achieving the production in vitro of functional organs that could be efficient substitutes for donor organ transplantation in the future. Finally, induction of morphogenesis with symmetry breaking signaling will provide a general framework that may be extended to the organization of other three-dimensional biological systems.