In addition to system-wide defects with Bptf deletion, there could be specific defects in individual signal transduction pathways within the embryo or in the ability of the embryo to receive growth signals from the extra-embryonic tissues or the surrounding decidua. To identify potential Bptf-dependent signaling pathways we focused on its role in specifying the DVE. The pre-gastrulation embryo uses three well-known signaling pathways, the WNT/β-catenin, FGF/MAPK and Nodal/Smad pathways, to establish A-P asymmetry [29]. The three pathways can be distinguished by different A-P phenotypes. In mutants of FGF/MAPK signaling the epiblast has severe proliferation defects, do not specify primitive endoderm, are quickly reabsorbed and the blastocysts do not outgrow when grown in culture [30],[44],[59],[60]. Mutations in the WNT/β-catenin, but not Nodal/Smad pathways, develop the DVE and in some cases the AVE [50], [61]–[63]. The ability of the Bptf embryos to form blastocyst outgrowths, specify the primitive endoderm, but not form the DVE is reminiscent of mutants in the Nodal/Smad signaling pathway rather than a defect in FGF/MAPK or WNT/β-catenin signaling (Table S2).
