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Molecular and Cellular Biology, May 2009, p. 2748-2761, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01391-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Trophoblast Stem Cell Maintenance by Fibroblast Growth Factor 4 Requires MEKK4 Activation of Jun N-Terminal Kinase {triangledown} ,{dagger}

Amy N. Abell,* Deborah A. Granger,{ddagger} Nancy L. Johnson,{ddagger} Nicole Vincent-Jordan, Christopher F. Dibble, and Gary L. Johnson*

Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7365

Received 4 September 2008/ Returned for modification 20 November 2008/ Accepted 9 March 2009

Trophoblast differentiation during placentation involves an epithelial-mesenchymal transition (EMT) with loss of E-cadherin and gain of trophoblast invasiveness. Mice harboring a point mutation that renders inactive the mitogen-activated protein kinase kinase kinase MEKK4 exhibit dysregulated placental development with increased trophoblast invasion. Isolated MEKK4 kinase-inactive trophoblast stem (TS) cells cultured under undifferentiating, self-renewing conditions in the presence of fibroblast growth factor 4 (FGF4) display increased expression of Slug, Twist, and matrix metalloproteinase 2 (MMP2), loss of E-cadherin, and hyperinvasion of extracellular matrix, each a hallmark of EMT. MEKK4 kinase-inactive TS cells show a preferential differentiation to Tpbp{alpha}- and Gcm1-positive trophoblasts, which are indicative of spongiotrophoblast and syncytiotrophoblast differentiation, respectively. FGF4-stimulated Jun N-terminal kinase (JNK) and p38 activity is markedly reduced in MEKK4 kinase-inactive TS cells. Chemical inhibition of JNK in wild-type TS cells induced a similar EMT response as loss of MEKK4 kinase activity, including inhibition of E-cadherin expression and increased expression of Slug, MMP2, Tpbp{alpha}, and Gcm1. Chromatin immunoprecipitation analyses revealed changes in AP-1 composition with increased Fra-2 and decreased Fra-1 and JunB binding to the regulatory regions of Gcm1 and MMP2 genes in MEKK4 kinase-inactive TS cells. Our results define MEKK4 as a signaling hub for FGF4 activation of JNK that is required for maintenance of TS cells in an undifferentiated state.

* Corresponding author. Mailing address for Amy N. Abell: Department of Pharmacology, 1012 Mary Ellen Jones Bldg., CB 7365, Chapel Hill, NC 27599-7365. Phone: (919) 843-3256. Fax: (919) 966-5640. E-mail: amy_abell{at}med.unc.edu. Mailing address for Gary L. Johnson: Department of Pharmacology, 1108 Mary Ellen Jones Bldg., CB 7365, Chapel Hill, NC 27599-7365. Phone: (919) 843-3107. Fax: (919) 966-5640. E-mail: glj{at}med.unc.edu

{triangledown} Published ahead of print on 16 March 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} D.A.G. and N.L.J. contributed equally to this work.

Molecular and Cellular Biology, May 2009, p. 2748-2761, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01391-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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