Due to the presence of all FGFRs in the epithelium
Due to the presence of all FGFRs in the epithelium, there are several FGFs ligands that could be binding to these FGF receptors, namely FGFs 1–4, 8–10, 16 and 18–20. By evaluating the known roles of FGFs in epithelial-mesenchymal interactions and in bone development, this list can be reduced. For example, studies in the limb show that FGF10 in the mesenchyme is required for epithelial thickening and induction of FGF8 in the epithelium (Ohuchi et al., 1997). It is therefore possible that FGFs 8 and 10 are expressed early in conjunctival papillae development. FGF8 binds to FGFR1c whereas FGF10 binds to FGFR1b and 2b. FGF2, 4 and 18 are involved in ossification (Kim et al., 1998; Rice et al., 2000; Ohbayashi et al., 2002). FGF2 binds to all FGFRs except for 2b. FGF 4 binds to all ‘c’ isoforms whereas FGF18 binds to FGFR2c and 3c. The scaleless mutant chicken (sc/sc) lacks scales, feathers and also has only 2–4 scleral ossicles (Blanck et al., 1981). A mutation in FGF20 was recently identified in this mutant (Wells et al., 2012). FGF20 binds to FGFR1c and 2c (Eswarakumar et al., 2005) which are expressed in the epithelium and the mesenchyme during phases 1 and 2. Thus, the most likely FGFs involved in scleral ossicle development are FGFs 2, 4, 8, 10, 18 and 20.
Conclusions This study identifies another potentially important gene family, namely the FGF family, in the development of the scleral ossicle system. We show that both ‘b’ and ‘c’ isoforms of FGFRs 1–3 are expressed prior to and during conjunctival papillae development. Moreover, the umbelliferone of all FGFR isoforms in the conjunctival papillae and their contiguous region as well as the absence of expression from the inter-papillary region indicates that FGF-FGFR signalling is likely involved in the pre-patterning of the epithelium, as well as the subsequent development of the conjunctival papillae. During the ossicle induction phase (HH34-37), all FGFR isoforms become downregulated, showing that FGFRs are most likely not involved during the latter phase of ossicle induction. FGFR expression may reappear later at HH38/38.5 during stages of mineralization, however, these stages were beyond the scope of this research. Functional studies would help determine the role of FGFRs in the scleral ossicle system. Additionally, studies investigating the expression of FGF ligands in the scleral ossicle system would create a deeper understanding of the possible FGF/FGFR interactions. Furthermore, since FGFs often work with other morphogens such as BMP, HH and Wnt, studying how changes in FGF/FGFR affect BMP, HH, and Wnt expression as well as vasculature would provide insight into some of the interactions that govern the development of this fascinating system as well as the development of intramembranous bones and non-neurogenic placodes.
Conflicts of interest
Acknowledgements We thank Dr. G. Schoenwolf (University of Utah) for kindly providing the FGFR plasmids. This research was supported by the Natural Science and Engineering Research Council of Canada through a Discovery Grant to TFO (#328376). We also thank the reviewers for their time in evaluating this study and for their positive feedback.
Introduction Our knowledge of the molecular alterations that drive cancer progression and response to treatment has driven the development of novel target therapies. The initial FGF was reported from fibroblasts as a mitogen more than four decades ago (Gospodarowicz, 1974). The fibroblast growth factor-receptor axis (FGF-FGFR) is involved in signal transduction pathways that regulate cell proliferation, differentiation, embryonic development, migration, survival, angiogenesis and organogenesis (Beenken and Mohammadi, 2009, Ornitz and Itoh, 2015). Over the last years several mutations and alterations in FGF-FGFR have been reported in cancer (Brooks et al., 2012). Therefore it has the potential to become a new target for cancer therapy development (Ornitz and Itoh, 2015). Moreover, specific alterations of FGFR are more frequent in certain types of tumors, thus making FGFR a suitable biomarker. Several TKIs have been evolved in order to inhibit FGFR and VEGFR domains, which share similar structures. According to this, we hypothesize that a dual inhibition of both receptors is a potential beneficial combination. However, many of these multi-TKIs are less capable of achieving an efficient FGFR inhibition and also increase side effects. Nowadays, pharmaceutical companies are developing more potent FGFR TKIs.