Fig. 7. Proposed model for vHNF1 function in liver induction. At the competence/specification step, FOXA1/2/3 and vHNF1 cooperate to confer responsiveness of the ventral endoderm to FGF signals and to induce the typically hepatic specification markers Alb, Ttr and Afp. In this process, Foxa2 is directly downstream of FGFs (Zhang et al., 2004), whereas vHNF1 maintains Foxa factor expression and that of an as yet unidentified downstream target of the FGF pathway. In addition, GATA4/6 factors (not shown in this model) are directly induced by BMP2/4 and probably also by FGFs (Zaret, 2002) and have been proposed to mediate hepatic competence. At the budding step, a more complex regulatory network is established: FOXA2 induces Hex expression and is autoregulated, as HNF1. vHNF1 has a preeminent role in this transcriptional circuit by inducing Hnf4a, Hnf6 (Poll et al., 2006), Hnf1a (Kyrmizi et al., 2006), Foxa3 (this study) (Hiemisch et al., 1997) and by maintaining Foxa2 expression (Kyrmizi et al., 2006). This regulatory circuit becomes highly interconnected and integrates additional regulators at later stages (Kyrmizi et al., 2006) to sustain the expression of differentiated hepatic functions. Dashed arrows indicate epistatic relationships.