Nuclear Factor I-C Links Platelet-Derived Growth Factor and Transforming Growth Factor β1 Signaling to Skin Wound Healing Progression

Abstract

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 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-␤ 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.

Extracellular deposition of matrilin-2 controls the timing of the myogenic program during muscle regeneration

“…Our interpretation of a regulatory interplay between Nfix and cell cycle inhibitors, such as p21, is also supported by a previously described role of Nfix in the regulation of mitogenic pathways in other cell types (Nebl et al, 1994). Our conclusions are also in line with prior observations of regulatory relationships between TGF-b and other Nfi species (Plasari et al, 2009;Plasari et al, 2010) and of BMP7 and Matn2 (Ichikawa et al, 2008) to control the timing of skin-wound healing. In keeping with these findings, we observed severe wound-healing defects in Matn2 2/2 mice on a C57BL/6 genetic background (F. Deák and I.…”

“…Nfi proteins have been implicated in the control of adult stem cells and tissue regeneration in connection with TGF-b signaling (Plasari et al, 2009;Plasari et al, 2010). Nfix has been shown to drive a transcriptional switch from embryonic to fetal myogenesis in vivo and in C2 culture by suppressing the effect of Nfia and activating fetal muscle genes (Messina et al, 2010).…”

“…Accordingly, other members of the NFI family have been implicated in other regenerative processes of adult tissue in the context of TGF-b signaling. For instance, Nfic has been implicated in tooth morphogenesis, skin-wound healing and the onset of the follicle cycle leading to hair regeneration (Lee et al, 2009;Plasari et al, 2009;Plasari et al, 2010). An NFIC isoform was shown to harbor a TGF-b-responsive domain, and NFI-binding sites acting as TGF-b-responsive elements have been reported in several other ECM genes (Alevizopoulos et al, 1995;Alonso et al, 1996;Iozzo et al, 1997).…”

Nuclear Factor I-C Regulates TGF-β-dependent Hair Follicle Cycling*

“…These abnormalities have been associated with a decreased proliferation of NFI-C-lacking dental cells due to the overexpression of transforming growth factor ␤1 (TGF-␤1) (8). In addition, we have also shown that NFI-C deficiency affects the normal progression of the skin wound healing process, which has been linked to altered platelet-derived growth factor (PDGF) and TGF-␤ signaling in the knockout animals (9).…”

“…For instance, PDGF, a potent chemotactic agent for macrophages, is known to activate the growth of telogen follicles (49). We recently found that NFI-C is involved in the inflammatory phase of the skin healing process (9). The PDGF and TGF-␤1 pathways were both found to be affected by the lack of NFI-C, and the increased expressions of PDGF and its receptor ␣ chain were linked to an increased infiltration of macrophages in the skin wounds of knock-out mice.…”