S04-04 Mechanisms regulating differentiation onset in the embryonic axis and ES cells

During development of the vertebrate embryo neuronal differentiation and neural patterning take place progressively as the spinal cord is generated and the body axis elongates. Fibroblast Growth Factor (FGF) signalling maintains the undifferentiated cell state of axial progenitor cells in the stem zone/tailbud. As cells leave this region they encounter retinoic acid (RA), provided by the segmenting paraxial mesoderm, which now inhibits FGF signalling and drives differentiation. Here we present data demonstrating the conservation of this FGF/RA differentiation switch throughout body axis extension and reveal how this is elaborated in the tail bud to arrest elongation and so define body axis length. Analysis of mouse embryonic stem (ES) cell differentiation indicates that following a period of endogenous FGF activity, which is required for loss of self-renewal, RA also acts by attenuating FGF signalling to drive neural differentiation. However, exposure to retinoic acid or blocking FGFR signalling can also accelerate non-neural ES cell differentiation. These findings indicate that the FGF/RA switch is a conserved and generic signalling mechanism mediating differentiation progression in embryos and ES cells.