Both Fgf and retinoid signalling promote embryonic stem (ES) cell differentiation, but how these signalling pathways interact is poorly understood. Kate Storey and colleagues now report that endogenous retinoid signalling induces ES cell differentiation by creating a distinct Fgf signalling signature (see p. ). The researchers show that the rapid induction of Fgf8 by retinoic acid (RA) initially increases Fgf/Erk signalling in mouse ES cells; a more gradual repression of Fgf4 by RA subsequently decreases Fgf/Erk signalling. This dual action may explain why RA is such a potent differentiation agent, first ensuring the loss of ES cell self-renewal by increasing Erk signalling and then inducing the onset of somatic differentiation by inhibiting Fgf signalling. Importantly, the researchers show that RA or Fgfr inhibition increases the expression of neural and non-neural genes in primitive ectoderm-like cells in vitro and promotes neural differentiation in the chick embryonic axis, which suggests that the second RA action is a conserved, generic differentiation mechanism.
