The p53 Family Coordinates Wnt and Nodal Inputs in Mesendodermal Differentiation of Embryonic Stem Cells

In this study, we outline a regulatory network that involves the p53 tumor suppressor family and the Wnt pathway acting together with the TGF-β pathway in mesendodermal differentiation of mouse and human embryonic stem cells. Knockout of all three members, p53, p63, and p73, shows that the p53 family is essential for mesendoderm specification during exit from pluripotency in embryos and in culture. Wnt3 and its receptor Fzd1 are direct p53 family target genes in this context, and induction of Wnt signaling by p53 is critical for activation of mesendodermal differentiation genes. Globally, Wnt3-activated Tcf3 and nodal-activated Smad2/3 transcription factors depend on each other for co-occupancy of target enhancers associated with key differentiation loci. Our results therefore highlight an unanticipated role for p53 family proteins in a regulatory network that integrates essential Wnt-Tcf and nodal-Smad inputs in a selective and interdependent way to drive mesendodermal differentiation of pluripotent cells. [Display omitted] •p53/63/73 family proteins redundantly enable mesendodermal differentiation of ESCs•p53/63/73 triple knockout leads to early defects in mouse embryo development•The p53 family activates Wnt expression and licenses mesendodermal differentiation•p53-Wnt-Tcf3 and Nodal-Smad2/3 pathways jointly activate mesendodermal enhancers Massagué and colleagues show that the p53/63/73 family is essential for mesendoderm specification in embryonic stem cells. The p53 family transcriptionally activates the Wnt pathway in human and mouse ESCs to coordinate Wnt-Tcf and nodal-Smad inputs for mesendodermal differentiation of ESCs in vitro and in the embryo.