Fibroblast Growth Factor 22 Is Not Essential for Skin Development and Repair but Plays a Role in Tumorigenesis Monika Jarosz1, Luisa Robbez-Masson 1 , Athina-Myrto Chioni1, Barbara Cross2, Ian Rosewell2, Richard Grose1* 1 Centre for Tumour Biology, Barts Cancer Institute – a Cancer Research UK Centre of Excellence, Queen Mary University of London, London, United Kingdom, 2 Biological Services, Clare Hall Laboratories, Cancer Research UK London Research Institute, South Mimms, Herts, United Kingdom Abstract Fibroblast Growth Factors play critical roles during development, tissue homeostasis and repair by controlling cell proliferation, survival, migration and differentiation. Of the 22 mammalian FGFs, FGF22, a member of the FGF7/10/22 subfamily, has been shown to have a clear role in synaptogenesis, but its roles in other tissues have not been studied. We have investigated the in vivo functions of FGF22 in mice. Fgf22 animals were viable, fertile and did not display any obvious abnormalities. Despite the known expression profile of FGF22 in the skin, no differences in either skin or pelage were observed, demonstrating that FGF22 is dispensable during embryogenesis and in unchallenged adult skin. Mice lacking FGF22 were able to heal acute wounds just as efficiently as wild type mice. However, classical two-step skin carcinogenesis challenge revealed that FGF22 mice developed fewer papillomas than wild type controls, suggesting a potential pro-oncogenic role for FGF22 in the skin. Citation: Jarosz M, Robbez-Masson L, Chioni A-M, Cross B, Rosewell I, et al. (2012) Fibroblast Growth Factor 22 Is Not Essential for Skin Development and Repair but Plays a Role in Tumorigenesis. PLoS ONE 7(6): e39436. doi:10.1371/journal.pone.0039436 Editor: Zhongjun Zhou, The University of Hong Kong, Hong Kong Received November 29, 2011; Accepted May 21, 2012; Published June 21, 2012 Copyright: 2012 Jarosz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This research was funded by Cancer Research UK, The Wellcome Trust (076678/Z/05/Z) and the Trustees of St Barts and The London Charitable Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: r.p.grose@qmul.ac.uk Introduction Fibroblast Growth Factors (FGFs) are a large family of 22 signalling molecules, responsible for regulating a range of cellular processes including proliferation, survival, migration, differentia- tion and response to injury [1]. Their various roles have been delineated through a large number of genetically modified mouse studies (reviewed in [2]). They act, for the most part, as secreted growth factors, which bind to receptor tyrosine kinases on nearby cells. FGFs can be grouped into subfamilies, based on sequence similarity and receptor specificity [1,3,4]. The biological activities of FGFs are mediated by high affinity cell surface tyrosine kinase receptors. FGF7/10/22 subfamily members activate two main receptors: FGFR1b and FGFR2b, although they signal preferentially, and exclusively in the case of FGF7, via FGFR2b [4,5]. Striking phenotypic similarities between fgf10 and fgfr2b knockout mice [6,7,8], together with rather modest phenotypes of fgf7 [9] and fgfr1b [10] knockout mice, have established the FGF10-FGFR2b axis as a key ligand-receptor partnership in embryogenesis. FGF22 is a relatively understudied member of the FGF7/10/22 subfamily [11]. In the skin, FGFs 7, 10 and 22 act predominately on cells of epithelial origin but, uniquely, FGF22 is expressed by epithelial cells [12], suggesting a cell autonomous role. Expression of FGF22 is relatively restricted. It first was detected, by Northern blot, in placenta, brain and skin [11]. In murine skin, expression of FGF22 begins at embryonic day 16.5, as determined by RNase protection assay [12]. In adult mouse skin, FGF22 is expressed in the inner root sheath (IRS) of the hair follicle [11] and in the interfollicular epidermis [12]. During hair development, the dermal papilla, a cluster of specialised mesenchymal cells within the dermis, signals to epidermal follicular stem cells to proliferate and differentiate into IRS, medulla and cortex cells, which together with the cuticle cells undergo terminal differentiation to form the mature hair fibre [13]. FGF7 and FGF10 are expressed in the dermal papilla of the hair follicle [14] and fgf7 knockout mice displayed a mild hair phenotype, with male mice developing greasy, matted hair with age [9]. Furthermore, transgenic mice overexpressing FGF7 in the epidermis demonstrated abnormal patterns of hair growth [15], and subcutaneous or intraperitoneal injections of recombinant FGF7 into nude mice stimulated hair growth by extending the anagen phase of the hair cycle [16]. Since both fgf10 and fgfr2b knockout mice die at birth, their hair phenotype is hard to study. Nevertheless, late stage fgfr2b knockout embryos showed a reduction in hair follicle development, with significantly fewer, developmentally retarded, hair follicles relative to wild type littermates [17]. Skin grafting studies, using late stage fgfr2b and wild type foetuses, showed that FGFR2b signalling was crucial for normal epidermal growth and development as well as for subsequent hair follicle morphogenesis [18]. Transgenic mice expressing dominant-negative FGFR2b in differentiating hair keratinocytes developed abnormally thin, but otherwise normal, hairs characterised by single columns of medulla cells in PLoS ONE | www.plosone.org 1 June 2012 | Volume 7 | Issue 6 | e39436