A) Beginning around the 16-cell stage, the HIPPO pathway is active in the ICM, where it represses expression of TE genes, such as Cdx2 and Sox2. The HIPPO pathway is inactive in the TE, enabling the transcriptional regulation of both ICM and TE genes in parallel (WWTR1 omitted for simplicity, please see text for details). B) At later stages, CDX2 reinforces the first cell fate decision by regulating expression of later-acting TE and ICM genes, such as Eomes and Oct4/Nanog, and GATA6 also helps repress Nanog in the TE. Simultaneously, OCT4 helps repress TE genes in some ICM cells. Please see text for relevant citations.