Nuclear Factor I-C Links Platelet-Derived Growth Factor and Transforming Growth Factor 1 Signaling to Skin Wound Healing Progression†

Transforming growth factor (TGF-) and platelet-derived growth factor A (PDGF) 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- 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-1. Misregulated genes were prominently overrepresented by regulators of connective tissue inflamma-tion 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- 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. The mammalian nuclear factor I (NFI) family of transcrip-tion-replication factors is encoded by four genes, NFI-A