Figure 3: Maintenance of the TSC niche in mice. (a) Multipotency and proliferation of trophoblast is regulated by trophoblast–epiblast interactions. Fgf4 and Fgfr2 are specifically expressed in the ICM/epiblast and trophoblasts, respectively. Due to Fgf4/Fgfr signaling, the polar trophectoderm cells overlying the ICM continue to proliferate and retain the expression of Cdx2. Bmp4 can induce Wnt3 for amplifying Nodal expression in the epiblast. Nodal in turn induces Fgf4 to regulate Bmp4 expression in the ExE. Thus, the four factors form a signaling circuitry at the ExE–Epi interface. (b) Fgf4-Erk pathway to regulate trophoblast multipotency. Fgf4/Fgfr signal promotes Erk phosphorylation, which activates the transcription of Esrrb and Sox2, thereby enhancing transcriptional networks of TSC self-renewal. (c) Occupancies of multipotency factors on the promoter region of target genes for transcription. For example, Tfap2c, Smarca4, Eomes, Elf5, and Cdx2 are enriched in Elf5. TK: Tyrosine kinase; ICM: Inner cell mass; TSC: Trophoblast stem cell; ExE: Extraembryonic ectoderm; Epi: Epiblast.