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Regulation of the State of Pluripotency is Critical for Lineage Specification and Embryonic Development

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thesis
posted on 13.12.2012, 00:00 by Jackson A. Hoffman
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.

History

Advisor

Merrill, Bradley J.

Department

Biochemistry and Molecular Genetics

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Committee Member

Frolov, Maxim Lau, Lester Tyner, Angela Schmidt, Jennifer

Submitted date

2012-08

Language

en

Issue date

13/12/2012