Mouse genetics identifies unique and overlapping functions of fibroblast growth factor receptors in keratinocytes.

Michael Meyer,David M Ornitz,Fumimasa Kubo,Lin Chen,Haruka Iizuka,Catharina Sänger,Marko Jukic,Sabine Werner,Maya Ben‐Yehuda Greenwald,Theresa Rauschendorfer

doi:10.1111/jcmm.14871

Abstract

Fibroblast growth factors (FGFs) are key regulators of tissue development, homeostasis and repair, and abnormal FGF signalling is associated with various human diseases. In human and murine epidermis, FGF receptor 3 (FGFR3) activation causes benign skin tumours, but the consequences of FGFR3 deficiency in this tissue have not been determined. Here, we show that FGFR3 in keratinocytes is dispensable for mouse skin development, homeostasis and wound repair. However, the defect in the epidermal barrier and the resulting inflammatory skin disease that develops in mice lacking FGFR1 and FGFR2 in keratinocytes were further aggravated upon additional loss of FGFR3. This caused fibroblast activation and fibrosis in the FGFR1/FGFR2 double‐knockout mice and even more in mice lacking all three FGFRs, revealing functional redundancy of FGFR3 with FGFR1 and FGFR2 for maintaining the epidermal barrier. Taken together, our study demonstrates that FGFR1, FGFR2 and FGFR3 act together to maintain epidermal integrity and cutaneous homeostasis, with FGFR2 being the dominant receptor.

Highlights

The defect in the epidermal barrier and the resulting inflammatory skin disease that develops in mice lacking FGFR1 and FGFR2 in keratinocytes were further aggravated upon additional loss of FGF receptor 3 (FGFR3)
Our study demonstrates that FGFR1, FGFR2 and FGFR3 act together to maintain epidermal integrity and cutaneous homeostasis, with FGFR2 being the dominant receptor
Characterized by progressive loss of hair follicles and sebaceous glands and development of chronic skin inflammation.[4,6,7]. This finding demonstrates that FGFR1 signalling is unmasked in the absence of FGFR2, probably through FGF10/FGF22 signalling to the b splice variant of FGFR1.2,4 The phenotype of the double mutant mice shows many similarities to the skin inflammation that occurs in patients with the chronic inflammatory skin disease atopic dermatitis (AD).[4,6,7,8]. It results from a defect in the epidermal barrier that is caused at least in part by decreased expression of major tight junction components that are under direct control of FGFR signalling in keratinocytes,[4,6,7,8] We showed that different types of immune cells are attracted and/ or activated upon establishment of the barrier defect, and growth factors and cytokines secreted by immune cells and fibroblasts caused keratinocyte hyperproliferation and epidermal thickening.[4,6,7,8]

Summary

| MATERIALS AND METHODS

Mice lacking FGFR1 and FGFR2 in keratinocytes (K5-R1/R2 mice) were previously described.[4,6,7,8,14] To generate mice lacking a functional FGFR3 protein in keratinocytes, we mated mice with floxed. Cells were incubated in boric buffer (100 mmol/L boric acid, 75 mmol/L NaCl, 25 mmol/L sodium tetraborate, pH 8.5) for neutralization for 5 minutes and blocked using 1% BSA for 30 minutes, FIGURE 1 Verification of the FGFR3 knockout in the mutant epidermis and in isolated primary keratinocytes A, Breeding scheme for the generation of mice lacking FGFR1, FGFR2 and FGFR3 in keratinocytes (K5-R1/R2/R3 mice).

C Keratinocytes

| DISCUSSION

Findings

E Epidermis