13-P053 Signaling factors in the specification of the cochlear tonotopic gradient

ectoderm/extraembryonic ectoderm in the peri-implantation embryos, have the capacity to self-renew in the presence of FGF4 and mouse embryonic fibroblasts (MEFs). Using an in vitro system of embryonic stem (ES) cells, we have reported that the trophoblast lineage can be specified by activation of Cdx2. During differentiation, cells can adopt stem cell fate in the presence of FGF4/MEFs, otherwise undergo terminal differentiation. To understand the transcriptional regulatory network that determines stem cell fate downstream of FGF/MEF signals, we screened for transcription factors (TFs) regulated by FGF4/MEFs during the trophoblast differentiation of ES cells. The expression of trophoblast-specific TFs, Cdx2, Eomes and Elf5, as well as preexisting TFs, Esrrb and Sox2, was enhanced in the presence of FGF4/MEFs. Particularly, the expression of Esrrb and Sox2 is highly dependent on FGF4 and, of great significance, combined expression of both TFs allowed for prolonged self-renewal in the absence of FGF4. Further studies elucidated that they function as downstream effectors of FGF signaling for the activation of trophoblast-specific TF module composed of Cdx2, Eomes and Elf5. Interestingly, Esrrb and Sox2 regulate the distinctly different transcriptional network in TS cells from that in ES cells, in which they are components of the core transcriptional regulatory circuitry downstream of the LIF signaling pathway. Our results provide a framework to understand how the cellular context affects the mode of action of TFs.