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Fibroblast Growth Factor Receptors 1 and 2 in Keratinocytes Control the Epidermal Barrier and Cutaneous Homeostasis

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Fibroblast Growth Factor Receptors 1 and 2 in Keratinocytes Control the Epidermal Barrier and Cutaneous Homeostasis Washington University School of Medicine Digital Commons@Becker Open Access Publications 2010 Fibroblast growth factor receptors 1 and 2 in keratinocytes control the epidermal barrier and cutaneous homeostasis Jingxuan Yang Michael Meyer Anna-Katharina Müller Friederike Böhm Richard Grose See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Authors Jingxuan Yang, Michael Meyer, Anna-Katharina Müller, Friederike Böhm, Richard Grose, Tina Dauwalder, Francois Verrey, Manfred Kopf, Juha Partanen, Wilhelm Bloch, David M. Ornitz, and Sabine Werner JCB: Article Fibroblast growth factor receptors 1 and 2 in keratinocytes control the epidermal barrier and cutaneous homeostasis 1 1 1 1 2 3 Jingxuan Yang, Michael Meyer, Anna-Katharina Müller, Friederike Böhm, Richard Grose, Tina Dauwalder, Downloaded from https://rupress.org/jcb/article-pdf/188/6/935/807652/jcb_200910126.pdf by Washington University In St. Louis Libraries user on 16 December 2019 Francois Verrey,3 Manfred Kopf,4 Juha Partanen,5 Wilhelm Bloch,6 David M. Ornitz,7 and Sabine Werner1 1Department of Biology, Institute of Cell Biology, Eidgenössische Technische Hochschule Zurich, 8093 Zurich, Switzerland 2Centre for Tumour Biology, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London SW3 6JB, England, UK 3Institute of Physiology and Center for Integrative Human Physiology, University of Zurich, 8057 Zurich, Switzerland 4Department of Environmental Sciences, Institute of Integrative Biology, Eidgenössische Technische Hochschule Zurich, 8952 Schlieren, Switzerland 5Institute of Biotechnology, Viikki Biocenter, 00014 Helsinki, Finland 6Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, 50933 Cologne, Germany 7Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110 ibroblast growth factors (FGFs) are master regula- skin disease. The defective barrier causes activation of tors of organogenesis and tissue homeostasis. In this keratinocytes and epidermal T cells, which produce F study, we used different combinations of FGF recep- interleukin-1 family member 8 and S100A8/A9 pro- tor (FGFR)-deficient mice to unravel their functions in the teins. These cytokines initiate an inflammatory response skin. Loss of the IIIb splice variants of FGFR1 and FGFR2 and induce a double paracrine loop through produc- in keratinocytes caused progressive loss of skin append- tion of keratinocyte mitogens by dermal cells. Our ages, cutaneous inflammation, keratinocyte hyperpro- results identify essential roles for FGFs in the regulation liferation, and acanthosis. We identified loss of FGF- of the epidermal barrier and in the prevention of induced expression of tight junction components with cutaneous inflammation, and highlight the importance subsequent deficits in epidermal barrier function as the of stromal–epithelial interactions in skin homeostasis mechanism underlying the progressive inflammatory and disease. Introduction FGFs comprise a family of 22 polypeptides that regulate ligand-binding specificities (Ornitz and Itoh, 2001). For example, THE JOURNAL OF CELL BIOLOGY migration, proliferation, differentiation, and survival of different the IIIb splice variant of FGFR2 (FGFR2IIIb) is a high-affinity cell types. They exert these functions through activation of receptor for FGF7, FGF10, and FGF22, whereas the IIIc variant four transmembrane tyrosine kinase receptors, designated (FGFR2IIIc) binds a variety of other FGF ligands (Zhang FGF receptor (FGFR) 1–4 (Ornitz and Itoh, 2001; Beenken et al., 2006). and Mohammadi, 2009). Further complexity is achieved by Previous studies revealed important roles of FGFs in alternative splicing in the FGFR genes. Of particular impor- development, homeostasis, and repair of the skin (Steiling tance is alternative splicing in the third immunoglobulin-like and Werner, 2003). Several FGFs are expressed in this tissue, domain of FGFR1-3, which generates IIIb and IIIc vari- and most of them are up-regulated upon injury (Werner et al., ants of these receptors that are characterized by different 1992, 1993; Komi-Kuramochi et al., 2005). Of particular interest are ligands of FGFR2IIIb because transgenic mice J. Yang and M. Meyer contributed equally to this paper. expressing a dominant-negative mutant of this receptor Correspondence to Sabine Werner: [email protected] in keratinocytes showed epidermal atrophy, hair follicle Abbreviations used in this paper: ERK, extracellular signal-regulated kinase; FGFR, FGF receptor; FRS, FGFR substrate; GAPDH, glyceraldehyde 3-phosphate © 2010 Yang et al. This article is distributed under the terms of an Attribution– dehydrogenase; G-CSF, granulocyte colony-stimulating factor; H/E, hematoxylin/ Noncommercial–Share Alike–No Mirror Sites license for the first six months after the eosin; IL, interleukin; NF-B, nuclear factor B; PCNA, proliferating cell nuclear publication date (see http://www.rupress.org/terms). After six months it is available under a antigen; RPS29, ribosomal protein S29; TER, transepithelial electrical resistance; Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, TEWL, transepidermal water loss. as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). The Rockefeller University Press $30.00 J. Cell Biol. Vol. 188 No. 6 935–952 www.jcb.org/cgi/doi/10.1083/jcb.200910126 JCB 935 abnormalities, and impaired wound reepithelialization (Werner signaling in the latter. EGF activated these signaling pathways et al., 1994). However, the responsible receptors remain to in cells of both genotypes (Fig. 1 D). be identified, as the dominant-negative mutant blocks the action of all FGF receptors in response to common FGF Overlapping functions of FGFR1 ligands (Ueno et al., 1992). The abnormalities seen in these and FGFR2 in the skin animals were not observed in FGF7 knockout mice (Guo et al., Macroscopically, no obvious abnormalities were observed in 1996), which suggests functional redundancy among different K5-R1 mice at any stage of postnatal development (Fig. 2 B). FGFs and possibly FGF receptors. Indeed, expression studies In contrast, K5-R2 mice revealed a phenotype (Fig. 2 C) revealed that FGF10 and FGF22 are also expressed in normal that fully matches the abnormalities seen in mice lacking and wounded skin (Beer et al., 1997; Nakatake et al., 2001; FGFR2IIIb in keratinocytes (K5-R2IIIb mice; Grose et al., Downloaded from https://rupress.org/jcb/article-pdf/188/6/935/807652/jcb_200910126.pdf by Washington University In St. Louis Libraries user on 16 December 2019 Beyer et al., 2003). Together with FGF7, they can activate 2007). The latter show hair abnormalities, a reduction in the the “b” splice variants of FGFRs 1 and 2 (Zhang et al., 2006) number of hairs, and loss of sebaceous glands. The phenotype that are expressed in keratinocytes (Beer et al., 2000; Zhang was much more severe in the double knockout mice (Fig. 2 D), et al., 2004). In the case of FGF7 and FGF10, the activation whereas the loss of only one Fgfr2 allele in addition to both occurs in a paracrine manner because both ligands are produced Fgfr1 alleles did not cause obvious phenotypic abnormal- by fibroblasts in the dermal papilla and in the interfollicular ities (not depicted). All females and 60% of the males were dermis as well as by epidermal T cells (Werner et al., 1993; infertile, and both were much smaller than control littermates. Rosenquist and Martin, 1996; Jameson and Havran, 2007). They also progressively lost their hair and were hairless by In contrast, FGF22 is mainly expressed in the inner root sheath the age of 2–4 mo (Fig. 2 E). However, we did not observe of the hair follicle (FGF22; Nakatake et al., 2001) and most an increased mortality rate, and we were able to maintain the likely acts in an autocrine manner (Fig.1 A). animals for up to 2 yr. To determine the function of these FGFs and their recep- tors in the skin, we generated mice lacking FGFR1, FGFR2, FGFR1IIIb cooperates with FGFR2IIIb in or both receptors in keratinocytes. Our results revealed that the regulation of epidermal homeostasis these receptors cooperate to maintain the epidermal barrier To identify the splice variant that cooperates with FGFR2 in and cutaneous homeostasis. keratinocytes, we generated mice lacking FGFR1IIIb in all cells and FGFR2 in keratinocytes (K5-R2/R1IIIb mice). FGFR1IIIb- Results deficient mice are phenotypically normal and do not display an obvious skin phenotype because only the IIIb exon of the Fgfr1 Generation of mice lacking FGFR1, FGFR2, gene was deleted in these mice, whereas all other FGFR1 splice or both receptors in keratinocytes variants are normally expressed (Zhang et al., 2004). The pheno- Mice with floxedFgfr1 (Pirvola et al., 2002) and Fgfr2 alleles type of K5-R2/R1IIIb mice was identical to the phenotype (Yu et al., 2003) were mated with transgenic mice expressing observed in K5-R1/R2 mice at the macroscopic (Fig. 2, E and F) Cre recombinase under the control of the keratin 5 (K5) and histological level (Fig. 3 E and not depicted). Therefore, promoter. This promoter allows excision of floxed alleles in we conclude that FGFR1IIIb and FGFR2IIIb cooperate in the basal cells of stratified epithelia after embryonic day 15.5 regulation of epidermal homeostasis. (Ramirez et al., 2004). The progeny of our breeding included mice lacking FGFR1, Loss of skin appendages
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