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

Area of Science:

• Developmental Biology
• Stem Cell Biology
• Molecular Genetics

Background:

• The p53 tumor suppressor family plays critical roles in cellular processes.
• Wnt and TGF-β signaling pathways are key regulators of embryonic development.
• Mesendodermal differentiation is a fundamental process in early embryogenesis.

Purpose of the Study:

• To elucidate the regulatory network governing mesendodermal differentiation.
• To investigate the interplay between the p53 family, Wnt, and TGF-β pathways.
• To understand the role of p53 in integrating signaling pathways during stem cell differentiation.

Main Methods:

• Utilizing knockout models of p53, p63, and p73 in mouse and human embryonic stem cells.
• Analyzing gene expression and signaling pathway activation.
• Investigating transcription factor binding and co-occupancy at target enhancers.

Main Results:

• The p53 family is essential for mesendoderm specification during exit from pluripotency.
• Wnt3 and Fzd1 are direct p53 family target genes, with p53-induced Wnt signaling critical for mesendodermal gene activation.
• Wnt3-activated Tcf3 and nodal-activated Smad2/3 transcription factors exhibit interdependent co-occupancy of target enhancers.

Conclusions:

• p53 family proteins play an unanticipated role in mesendodermal differentiation.
• A regulatory network integrating Wnt-Tcf and nodal-Smad signaling is orchestrated by the p53 family.
• This network selectively and dependently drives mesendodermal differentiation of pluripotent cells.