Nuclear factor I-C links platelet-derived growth factor and transforming growth factor beta1 signaling to skin wound healing progression.
Transforming growth factor beta (TGF-beta) and platelet-derived growth factor A (PDGFAlpha) 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-beta 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-beta1. 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-beta 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.
Plasari
Genta
G
Institute of Biotechnology, University of Lausanne, 1015 Lausanne, Switzerland.
Calabrese
Alessandra
A
Dusserre
Yves
Y
Gronostajski
Richard M
RM
McNair
Alan
A
Michalik
Liliane
L
Mermod
Nicolas
N
D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005109:Extracellular Matrix / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D008264:Macrophages / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D051839:NFI Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014945:Wound Healing
D016326:Extracellular Matrix Proteins; D051839:NFI Transcription Factors; D010982:Platelet-Derived Growth Factor; D053773:Transforming Growth Factor beta1; C075278:platelet-derived growth factor A