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


Tan, Frederick Eng How (2014) Brfl Post-Transcriptionally Regulates Pluripotency and Differentiation Responses Downstream of Erk MAP Kinase. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/MM53-XC23.


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.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:RNA binding proteins, stem cell biology, developmental biology
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Biochemistry and Molecular Biophysics
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Elowitz, Michael B.
Thesis Committee:
  • Stathopoulos, Angelike (chair)
  • Rothenberg, Ellen V.
  • Plath, Kathrin
  • Elowitz, Michael B.
Defense Date:19 May 2014
Funding AgencyGrant Number
Human Frontiers Science ProgramRGP0020/2012
Weston Havens FoundationUNSPECIFIED
David and Lucile Packard FoundationUNSPECIFIED
National Defense Science and Engineering Graduate Research FellowshipUNSPECIFIED
Record Number:CaltechTHESIS:05292014-234047875
Persistent URL:
Related URLs:
URLURL TypeDescription adapted for Ch.2-6: Brf1 posttranscriptionally regulates pluripotency and differentiation responses downstream of Erk MAP kinase material for published article in CaltechAUTHORS
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8434
Deposited By: Frederick Tan
Deposited On:31 May 2014 00:03
Last Modified:04 Oct 2019 00:05

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