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Molecular and Cellular Biology, November 2009, p. 6006-6017, Vol. 29, No. 22
0270-7306/09/$08.00+0     doi:10.1128/MCB.01921-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Nuclear Factor I-C Links Platelet-Derived Growth Factor and Transforming Growth Factor β1 Signaling to Skin Wound Healing Progression{triangledown} ,{dagger}

Genta Plasari,1,§ Alessandra Calabrese,1,§ Yves Dusserre,1 Richard M. Gronostajski,3 Alan Mcnair,1,{ddagger} Liliane Michalik,2 and Nicolas Mermod1*

Institute of Biotechnology, University of Lausanne, 1015 Lausanne, Switzerland,1 Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland,2 Department of Biochemistry and Developmental Genomics Group, New York State Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, New York 142033

Received 19 December 2008/ Returned for modification 24 March 2009/ Accepted 8 September 2009

Transforming growth factor β (TGF-β) and platelet-derived growth factor A (PDGFA) play a central role in tissue morphogenesis and repair, but their interplay remain poorly understood. The nuclear factor I C (NFI-C) transcription factor has been implicated in TGF-β signaling, extracellular matrix deposition, and skin appendage pathologies, but a potential role in skin morphogenesis or healing had not been assessed. To evaluate this possibility, we performed a global gene expression analysis in NFI-C–/– and wild-type embryonic primary murine fibroblasts. This indicated that NFI-C acts mostly to repress gene expression in response to TGF-β1. Misregulated genes were prominently overrepresented by regulators of connective tissue inflammation and repair. In vivo skin healing revealed a faster inflammatory stage and wound closure in NFI-C–/– mice. Expression of PDGFA and PDGF-receptor alpha were increased in wounds of NFI-C–/– mice, explaining the early recruitment of macrophages and fibroblasts. Differentiation of fibroblasts to contractile myofibroblasts was also elevated, providing a rationale for faster wound closure. Taken together with the role of TGF-β in myofibroblast differentiation, our results imply a central role of NFI-C in the interplay of the two signaling pathways and in regulation of the progression of tissue regeneration.

* Corresponding author. Mailing address: Laboratory of Molecular Biotechnology, Station 6, EPFL-FSB-LBTM, 1015 Lausanne, Switzerland. Phone: 41 (21) 693 61 51. Fax: 41 (21) 693 76 10. E-mail: Nicolas.Mermod{at}unil.ch

{triangledown} Published ahead of print on 14 September 2009.

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

§ These authors contributed equally to this work.

{ddagger} Present address: University of Dundee, Dundee, Scotland, United Kingdom.

Molecular and Cellular Biology, November 2009, p. 6006-6017, Vol. 29, No. 22
0270-7306/09/$08.00+0     doi:10.1128/MCB.01921-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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