Dynamics of FGF and its integration with other pathways during human germ layer differentiation

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Abstract Gastrulation is the stage of early embryonic development during which the body plan is established. Using the mouse as a model, it has been established that mammalian gastrulation is primarily regulated by BMP, FGF, WNT, and NODAL signaling pathways and disruption of these pathways can lead to developmental defects or early embryonic lethality which ay infest as infertility. However, it remains unclear how cells interpret multiple signaling pathways to make specific cell fate decisions. Moreover, findings in mice cannot directly be compare to human development. For example, disruption of FGF signaling at blastocyst stage leads to defects in visceral endoderm development in mice but not in human. Human pluripotent stem cells (hPSCs) have been an ideal model system to study gastrulation because they mimic many aspects of gastrulation and allow for high throughput, quantitative analysis and time resolved experiments in vitro. Using micropatterned hPSC gastrulation model and directed primitive streak like cell differentiation model, my data suggests that higher FGF/ERK signaling activity is spatially restricted to PSLCs and functional experiments that block FGF signaling results in a failure of PSLC differentiation as well as downregulation of WNT3 ligand expression. Based on this, my overarching hypothesis is that FGF/ERK signaling is spatially and temporally regulated by expression of FGF ligands and heparin sulfate proteogylcan (HSPG) modulators and act in parallel to BMP upstream of WNT and NODAL to create combined signaling patterns that induce different cell fate outcome. I will test this hypothesis by 1) determining how FGF activity is spactially and temporally regulated by FGF ligands and HSPG modulators, 2) dissecting the dynamics of multiple signaling activity underlying cell fate acquisition during in vitro gastrulation.