title: Brf1 posttranscriptionally regulates pluripotency and differentiation responses downstream of Erk MAP kinase.
abstract: AU-rich element mRNA-binding proteins (AUBPs) are key regulators of development, but how they are controlled and what functional roles they play depends on cellular context. Here, we show that Brf1 (zfp36l1), an AUBP from the Zfp36 protein family, operates downstream of FGF/Erk MAP kinase signaling to regulate pluripotency and cell fate decision making in mouse embryonic stem cells (mESCs). FGF/Erk MAP kinase signaling up-regulates Brf1, which 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. Enhancing Brf1 expression does not compromise mESC pluripotency but does preferentially regulate mesendoderm commitment during differentiation, accelerating the expression of primitive streak markers. Together, these studies demonstrate that FGF signals use targeted mRNA degradation by Brf1 to enable rapid posttranscriptional control of gene expression in mESCs.
authors.affiliation: Howard Hughes Medical Institute and Division of Biology and Departments of Bioengineering and Applied Physics, California Institute of Technology, Pasadena, CA 91125.
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Tan
authors.forename: Michael B
authors.initials: MB
authors.lastname: Elowitz
mesh_terms: D063307:AU Rich Elements / Q000235:genetics; D000818:Animals; D051817:Butyrate Response Factor 1; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000201:enzymology; D004707:Endoderm / Q000166:cytology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D006207:Half-Life; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D000071317:Nanog Homeobox Protein; D009687:Nuclear Proteins / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism
chemical_list: D051817:Butyrate Response Factor 1; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051816:Tristetraprolin; C497553:Zfp36 protein, mouse; C488431:Zfp36l1 protein, mouse; D005346:Fibroblast Growth Factors; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: AU-rich element RNA-binding proteins; developmental mechanisms; developmental signaling pathways; gene regulation dynamics; stem cell biology
references.citation: Development. 1998 Feb;125(4):753-65
references.pmid: 9435295
references.citation: Curr Biol. 1995 Jan 1;5(1):62-7
references.pmid: 7535172
references.citation: Cytokine Growth Factor Rev. 2005 Apr;16(2):233-47
references.pmid: 15863038
references.citation: Mol Cell Biol. 2006 Dec;26(24):9196-208
references.pmid: 17030620
references.citation: Development. 2011 Jan;138(1):3-8
references.pmid: 21138972
references.citation: Development. 1998 May;125(9):1747-57
references.pmid: 9521912
references.citation: Dev Cell. 2006 May;10(5):615-24
references.pmid: 16678776
references.citation: Nucleic Acids Res. 2006 Jan 03;33(22):7138-50
references.pmid: 16391004
references.citation: Am J Physiol Cell Physiol. 2011 Sep;301(3):C609-18
references.pmid: 21593445
references.citation: J Biol Chem. 2004 Jul 30;279(31):32393-400
references.pmid: 15187092
references.citation: Genes Dev. 1999 Jul 15;13(14):1834-46
references.pmid: 10421635
references.citation: PLoS One. 2011;6(6):e20773
references.pmid: 21695151
references.citation: Nat Genet. 2007 Apr;39(4):503-12
references.pmid: 17322878
references.citation: Development. 2010 Oct;137(20):3351-60
references.pmid: 20876656
references.citation: Nat Cell Biol. 2008 Mar;10(3):353-60
references.pmid: 18264089
references.citation: Nat Struct Mol Biol. 2013 Sep;20(9):1122-30
references.pmid: 23912277
references.citation: Nat Biotechnol. 2010 May;28(5):511-5
references.pmid: 20436464
references.citation: Dev Biol. 1997 Dec 15;192(2):614-29
references.pmid: 9441693
references.citation: Dev Biol. 2012 Nov 15;371(2):235-45
references.pmid: 22954964
references.citation: Mol Cell Biol. 2006 Oct;26(20):7539-49
references.pmid: 16908534
references.citation: Nat Immunol. 2010 Aug;11(8):717-24
references.pmid: 20622884
references.citation: Mol Cell Biol. 2003 Sep;23(18):6685-93
references.pmid: 12944492
references.citation: Cell. 2005 Mar 11;120(5):623-34
references.pmid: 15766526
references.citation: Nature. 2008 May 22;453(7194):519-23
references.pmid: 18497825
references.citation: Cell. 2003 Oct 31;115(3):281-92
references.pmid: 14636556
references.citation: Nat Protoc. 2006;1(1):302-7
references.pmid: 17406249
references.citation: Stem Cells. 2008 Nov;26(11):2759-67
references.pmid: 18687992
references.citation: Cell Signal. 2008 Dec;20(12):2165-73
references.pmid: 18585896
references.citation: Cell. 2003 May 30;113(5):631-42
references.pmid: 12787504
references.citation: J Neurosci. 1997 May 1;17(9):3024-37
references.pmid: 9096138
references.citation: Genes Dev. 2007 Oct 15;21(20):2545-57
references.pmid: 17938240
references.citation: Mol Cell Biol. 2004 Jul;24(14):6445-55
references.pmid: 15226444
references.citation: J Immunol. 2005 Jan 15;174(2):953-61
references.pmid: 15634918
references.citation: Mol Cell Biol. 2009 May;29(10):2762-76
references.pmid: 19307312
references.citation: Crit Rev Biochem Mol Biol. 2005 Jan-Feb;40(1):21-73
references.pmid: 15804624
references.citation: Nat Biotechnol. 2003 Feb;21(2):183-6
references.pmid: 12524553
references.citation: Mol Immunol. 2008 Jan;45(1):13-24
references.pmid: 17606294
references.citation: Mol Cell Biol. 2000 Feb;20(3):760-9
references.pmid: 10629032
references.citation: Dev Cell. 2011 Dec 13;21(6):1005-13
references.pmid: 22172669
references.citation: J Biol Chem. 2012 Aug 31;287(36):30507-17
references.pmid: 22787153
references.citation: J Biol Chem. 2004 Mar 26;279(13):12974-9
references.pmid: 14711832
references.citation: Nat Methods. 2013 Jan;10(1):71-3
references.pmid: 23160280
references.citation: FEBS Lett. 2008 Jun 18;582(14):1977-86
references.pmid: 18342629
references.citation: Mol Biol Cell. 2011 Aug 15;22(16):2875-85
references.pmid: 21737689
references.citation: Blood. 2011 Nov 24;118(22):5732-40
references.pmid: 21917750
references.citation: Cell. 2003 May 30;113(5):643-55
references.pmid: 12787505
references.citation: Nature. 2006 Aug 3;442(7102):533-8
references.pmid: 16767105