Regulation of the State of Pluripotency is Critical for Lineage Specification and Embryonic Development
Hoffman, Jackson A.
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My research has focused on elucidating the function of Tcf7l1 in embryonic stem cells (ESC) and the pluripotent cells of the mouse embryo. Previous work has revealed that Tcf7l1 is a component of the Oct4/Sox2/Nanog gene regulatory network (GRN) that regulates the pluripotency of ESC. My research has revealed that Tcf7l1 is a critical factor for coordinating the regulation of the pluripotency GRN with the onset of embryonic lineage specification. I found that Tcf7l1 was necessary for pluripotent cells to transition from a self-renewing state to a state that was primed for lineage specification. In the absence of Tcf7l1, this transition and subsequent lineage specification was delayed/defective. I was further able to show that this in vitro function was conserved during in vivo development of the mouse embryo. Tcf7l1-/- embryos exhibited prolonged and un-regulated expression of pluripotency factors, a delay in the initial induction of mesoderm specification, and a catastrophic disruption of the basic body plan. These data have revealed that Tcf7l1 is a novel negative regulator of pluripotency expressed in ESC and the embryo to facilitate the proper transition from self renewal to lineage specification during development. Importantly, my research takes a major step towards consolidating the understanding of the in vitro regulation of pluripotency with the actual function of the pluripotency GRN in vivo. I will also detail my work in developing a novel microfluidic device for in vitro culture of mouse embryos. Finally, I will discuss my engineering of a novel transgenic mouse model for inducible expression of the pluripotency factor Nanog and the discovery of its potential as a model for hepatocellular carcinoma.
Embryonic Stem Cells
Epiblast Stem Cells