Brfl Post-Transcriptionally Regulates Pluripotency and Differentiation Responses Downstream of Erk MAP Kinase

Author: Tan, Frederick Eng How

Year: 2014

Degree: Dissertation (Ph.D.)

Advisor: Elowitz, Michael B.

Committee Members: Stathopoulos, Angelike; Rothenberg, Ellen V.; Plath, Kathrin; Elowitz, Michael B.

Option: Biochemistry and Molecular Biophysics

DOI: 10.7907/MM53-XC23

Abstract

FGF/Erk MAP Kinase Signaling is a central regulator of mouse embryonic stem cell (mESC) self-renewal, pluripotency and differentiation. However, the mechanistic connection between this signaling pathway activity and the gene circuits stabilizing mESCs in vitro remain unclear. Here we show that FGF signaling post-transcriptionally regulates the mESC transcription factor network by controlling the expression of Brf1 (zfp36l1), an AU-rich element mRNA binding protein. Changes in Brf1 level disrupts the expression of core pluripotency-associated genes and attenuates mESC self-renewal without inducing differentiation. These regulatory effects are mediated by rapid and direct destabilization of Brf1 targets, such as Nanog mRNA. Interestingly, enhancing Brf1 expression does not compromise mESC pluripotency, but does preferentially regulate differentiation to mesendoderm by accelerating the expression of primitive streak markers. Together, these studies demonstrate that FGF signals utilize targeted mRNA degradation by Brf1 to enable rapid post-transcriptional control of gene expression.

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