Thisse, Bernard V.
Professor, Cell Biology
- PhD, Molecular Genetics, University of Strasbourg
- Postdoc, Developmental Biology, IGBMC_CNRS
- Postdoc, Developmental Biology, University of Oregon
Molecular control of embryonic development
From the fertilized egg to the fully differentiated organism, cells undergo proliferation, differentiation and morphogenesis. These different functions are controlled by sets of instructing signaling that have been conserved across evolution and that turn ON, OFF or that regulate the developmental programs required to form the different tissues and organs of a mature individual. During early embryonic development a handful of signaling pathways, activated by a small number of secreted factors acting as morphogens, are sufficient to pattern the growing embryos along antero-posterior and dorso-ventral axes and to induce a bilateral asymmetry defining a left and a right side.
Previous work of our lab has focused on the establishment of the dorso-ventral axis of the zebrafish embryo through the regulation of the activity of TGFbeta superfamily members, the Bone Morphogenetic Proteins (BMPs), by specific secreted antagonists and by the Fibroblast growth factors (FGFs) signaling pathway that regulates BMP signal transduction.
We also established that factors belonging to another group of the TGFbeta superfamily, the Nodal related factors, are patterning the embryo along the animal-vegetal axis therefore controlling the establishment of the definitive antero-posterior axis of the embryo.
Looking at interactions between these signaling pathways, we found that specific combinations of BMP and Nodal signaling can induce the different domain of the embryo, posterior head, trunk or tail, present along the antero-posterior axis. Finally we discovered that a complete embryonic axis, with all proper tissues and organs can be organized by instructing uncommitted pluripotent embryonic cells with two opposing gradients of BMP and of Nodal that generate the full spectrum of combination of these two signals.
Because the signaling pathways controlling early embryonic development have been conserved across evolution we predict that results obtained using zebrafish embryonic cells can be extrapolated to mammalian embryos. Therefore we are now trying to take control of aggregates of mouse embryonic stem cells (embryoid bodies), instructing them through experimentally engineered, spatially defined, morphogen gradients that should control fate and behavior of these pluripotent cells. Our ultimate goal is to use this approach to generate functional tissues and organs for application in Regenerative Medicine.
In parallel to this study, our lab is investigating the role of the Hippo signaling pathway in the control of early embryonic development. Hippo is a highly conserved pathway known to control organ size through the regulation of cell proliferation, cell death and cell differentiation. We recently discovered an unsuspected role for the transcriptional mediators of the Hippo pathway (YAP, TAZ, TEADs) and their regulators (VGL4s) in the control, at the transcriptional level, of the formation of the ciliated organ that acts as the Left-Right organizer of the embryo. Using Crispr/Cas9 editing technology as well as various methods of gain of function and of gene knockdowns we are dissecting the molecular mechanisms regulating the formation of the Left-Right organizer and through a comprehensive analysis of the transcriptome of the precursor cells of the Left-Right organizer in the different loss of function conditions we are characterizing the cascade of gene products involved in the formation and function of this organ.