Keratinocyte growth factor is required for hair development but not for wound healing.

Abstract

Keratinocyte growth factor (KGF), also known as fibroblast growth factor 7 (FGF7), is synthesized by skin fibroblasts. However, its mitogenic activity is on skin keratinocytes, where it is the most potent growth factor identified thus far. To explore KGF's function in vivo, we used embryonic stem cell technology to generate mice lacking KGF. Over time, their fur developed a matted appearance, very similar to that of the rough mouse, whose recessive mutation maps at or near the KGF locus on mouse chromosome 2. In contrast to the recently reported transforming growth factor-~ (TGF-~) and FGF5 knockouts, which showed defects in the follicle outer-root sheath and the hair growth cycle, respectively, the hair defect in the KGF knockout seemed to be restricted to the cells giving rise to the hair shaft. Thus, we have uncovered a third, and at least partially nonoverlapping, growth factor pathway involved in orchestrating hair follicle growth and/or differentiation. Surprisingly, the absence of KGF resulted in no abnormalities in epidermal growth or wound healing. This was true even when we engineered double knockout mice, null for both KGF and TGF-a, two factors that are increased dramatically in the normal wound-healing process. Whereas we found no evidence of compensatory changes at the mRNA level of wounded knockout mice, these data imply that the regulation of epidermal growth is complex and involves a number of growth stimulatory factors that go beyond what are thought to be the major paracrine and autocrine growth factors. We suggest that the redundancy in epidermal growth and wound healing is likely to stem from the vitality of these functions to the organism, a feature that is not a consideration for the hair follicle.

Fibroblast growth factor receptor 2 (Fgfr2) plays an important role in eyelid and skin formation and patterning

“…5K,L). It was shown previously that Fgf5-null (Hebert et al, 1994) and Fgf7-null (Guo et al, 1996) mice survived to adulthood, bearing a coat with longer hair or with matted appearance, respectively. Because both Fgf5 and Fgf7 have been shown to interact with Fgfr2, we were interested in evaluating how loss of these interactions might impact on skin and hair development in Fgfr2 ⌬III/⌬III mice.…”

“…Indeed, two previously reported Fgf-null mice exhibited abnormal hair formation. Fgf5-null mice exhibited defects in the hair growth cycle and developed abnormally longer hair 3 weeks after birth than wildtype controls (Hebert et al, 1994), while Fgf7 knockout mice displayed a rough or matted fur appearance (Guo et al, 1996). As the functions of many recently isolated members of FGF family have yet to be determined, it will be interesting to investigate if they are involved in skin formation and hair growth.…”

FGFR2IIIb signaling regulates thymic epithelial differentiation

“…Targeted disruption of the FGFR2IIIb gene or expression of a soluble dominant-negative form of this receptor results in a spectrum of developmental defects affecting multiple tissues/organs, including markedly hypoplastic thymi (Celli et al, 1998;De Moerlooze et al, 2000;Revest et al, 2001). Many of the sequelae of FGFR2IIIb deficiency are recapitulated in FGF10-deficient mice (Revest et al, 2001), but not FGF7-deficient mice (Guo et al, 1996), indicating a nonredundant role for FGF10 in these developmental processes.…”

Neu differentiation factor/heregulin induction by hepatocyte and keratinocyte growth factors

“…Using the same animal model of skin injury described by Werner et al (1992), we observed the induction of NDF during wound healing after the established peak of KGF induction, suggesting a direct link between the two events. While the epithelial speci®city of KGF is well-established in this model system, it is possible that other factors present at the wound site might stimulate NDF production, such as TGF-alpha (Guo et al, 1996), or heparin-binding EGF (Marikovsky et al, 1996). EGF itself is less likely to be involved, as no signi®cant induction of EGF mRNA was observed in this model system (S Werner, unpublished observations).…”