Members of the fibroblast growth factor (FGF) family have myriad functions during development of both non-vertebrate and vertebrate organisms. One of these family members, FGF10, is largely expressed in mesenchymal tissues and is essential for postnatal life because of its critical role in development of the craniofacial complex, as well as in lung branching. Here, we review the function of FGF10 in morphogenesis of craniofacial organs. Genetic mouse models have demonstrated that the dysregulation or absence of FGF10 function affects the process of palate closure, and FGF10 is also required for development of salivary and lacrimal glands, the inner ear, eye lids, tongue taste papillae, teeth, and skull bones. Importantly, mutations within the FGF10 locus have been described in connection with craniofacial malformations in humans. A detailed understanding of craniofacial defects caused by dysregulation of FGF10 and the precise mechanisms that underlie them offers new opportunities for development of medical treatments for patients with birth defects and for regenerative approaches for cancer patients with damaged gland tissues.

Laboratory of Transgenic Models of Diseases Czech Centre for Phenogenomics Institute of Molecular Genetics Czech Academy of Sciences Prague Czechia

Program in Craniofacial Biology Departments of Orofacial Sciences and Pediatrics Institute for Human Genetics University of California San Francisco San Francisco CA United States

Zobrazit více v PubMed

Alappat S. R., Zhang Z., Suzuki K., Zhang X., Liu H., Jiang R., et al. (2005). The cellular and molecular etiology of the cleft secondary palate in Fgf10 mutant mice. PubMed DOI

Alvarez Y., Alonso M. T., Vendrell V., Zelarayan L. C., Chamero P., Theil T., et al. (2003). Requirements for FGF3 and FGF10 during inner ear formation. PubMed DOI

Anderson J., Burns H. D., Enriquez-Harris P., Wilkie A. O., Heath J. K. (1998). Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand. PubMed DOI

Basson M. A., Echevarria D., Petersen Ahn C., Sudarov A., Joyner A. L., Mason I. J., et al. (2008). Specific regions within the embryonic midbrain and cerebellum require different levels of FGF signaling during development. PubMed DOI PMC

Bochukova E. G., Roscioli T., Hedges D. J., Taylor I. B., Johnson D., David D. J., et al. (2009). Rare mutations of FGFR2 causing apert syndrome: identification of the first partial gene deletion, and an Alu element insertion from a new subfamily. PubMed DOI

Chatzeli L., Gaete M., Tucker A. S. (2017). Fgf10 and Sox9 are essential for the establishment of distal progenitor cells during mouse salivary gland development. PubMed DOI PMC

Cruz C. V., Mattos C. T., Maia J. C., Granjeiro J. M., Reis M. F., Mucha J. N., et al. (2017). Genetic polymorphisms underlying the skeletal Class III phenotype. PubMed DOI

Domínguez-Frutos E., Vendrell V., Alvarez Y., Zelarayan L. C., López-Hernández I., Ros M., et al. (2009). Tissue-specific requirements for FGF8 during early inner ear development. PubMed DOI

El Agha E., Al Alam D., Carraro G., MacKenzie B., Goth K., De Langhe S. P., et al. (2012). Characterization of a novel fibroblast growth factor 10 (fgf10) knock-in mouse line to target mesenchymal progenitors during embryonic development. Königshoff M, editor. PubMed DOI PMC

Emmerson E., May A. J., Berthoin L., Cruz-Pacheco N., Nathan S., Mattingly A. J., et al. (2018). Salivary glands regenerate after radiation injury through SOX2-mediated secretory cell replacement. PubMed DOI PMC

Entesarian M., Dahlqvist J., Shashi V., Stanley C. S., Falahat B., Reardon W., et al. (2007). FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG). PubMed DOI

Eswarakumar V. P., Monsonego-Ornan E., Pines M., Antonopoulou I., Morriss-Kay G. M., Lonai P. (2002). The IIIc alternative of Fgfr2 is a positive regulator of bone formation. PubMed

Garg A., Zhang X. (2017). Lacrimal gland development: from signaling interactions to regenerative medicine: lacrimal gland development and regeneration. PubMed DOI PMC

Govindarajan V., Ito M., Makarenkova H. P., Lang R. A., Overbeek P. A. (2000). Endogenous and ectopic gland induction by FGF-10. PubMed DOI

Gromova A., Voronov D. A., Yoshida M., Thotakura S., Meech R., Dartt D. A., et al. (2017). Lacrimal Gland repair using progenitor cells: lacrimal gland repair with progenitor cells. PubMed DOI PMC

Hajihosseini M. K., Duarte R., Pegrum J., Donjacour A., Lana-Elola E., Rice D. P., et al. (2009). Evidence that Fgf10 contributes to the skeletal and visceral defects of an Apert syndrome mouse model. PubMed DOI

Hajihosseini M. K., Wilson S., De Moerlooze L., Dickson C. (2001). A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes. PubMed DOI PMC

Harada H., Kettunen P., Jung H. S., Mustonen T., Wang Y. A., Thesleff I. (1999). Localization of putative stem cells in dental epithelium and their association with Notch and FGF signaling. PubMed DOI PMC

Harada H., Toyono T., Toyoshima K., Yamasaki M., Itoh N., Kato S., et al. (2002). FGF10 maintains stem cell compartment in developing mouse incisors. PubMed

Hibberd C. E., Bowdin S., Arudchelvan Y., Forrest C. R., Brakora K. A., Marcucio R. S., et al. (2016). FGFR-associated craniosynostosis syndromes and gastrointestinal defects. PubMed DOI PMC

Hosokawa R., Oka K., Yamaza T., Iwata J., Urata M., Xu X., et al. (2010). TGF-beta mediated FGF10 signaling in cranial neural crest cells controls development of myogenic progenitor cells through tissue-tissue interactions during tongue morphogenesis. PubMed DOI PMC

Jaskoll T., Abichaker G., Witcher D., Sala F. G., Bellusci S., Hajihosseini M. K., et al. (2005). FGF10/FGFR2b signaling plays essential roles during in vivo embryonic submandibular salivary gland morphogenesis. PubMed DOI PMC

Jiang R., Lan Y., Chapman H. D., Shawber C., Norton C. R., Serreze D. V., et al. (1998). Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. PubMed DOI PMC

Juriloff D. M. (1982). Differences in frequency of cleft lip among the A strains of mice. PubMed DOI

Juriloff D. M., Harris M. J., McMahon A. P., Carroll T. J., Lidral A. C. (2006). Wnt9b is the mutated gene involved in multifactorial nonsyndromic cleft lip with or without cleft palate in A/WySn mice, as confirmed by a genetic complementation test. PubMed DOI

Kettunen P., Laurikkala J., Itäranta P., Vainio S., Itoh N., Thesleff I. (2000). Associations of FGF-3 and FGF-10 with signaling networks regulating tooth morphogenesis. PubMed

Knosp W. M., Knox S. M., Hoffman M. P. (2012). Salivary gland organogenesis. PubMed DOI

Lemmerling M. M., Vanzieleghem B. D., Dhooge I. J., Van Cauwenberge P. B., Kunnen M. F. (1999). The Lacrimo-Auriculo-Dento-Digital (LADD) syndrome: temporal bone CT findings. PubMed DOI

Lewandoski M., Sun X., Martin G. R. (2000). Fgf8 signalling from the AER is essential for normal limb development. PubMed DOI

Lombaert I., Knox S., Hoffman M. (2011). Salivary gland progenitor cell biology provides a rationale for therapeutic salivary gland regeneration: salivary gland regeneration using progenitor cells. PubMed DOI PMC

Makarenkova H. P., Hoffman M. P., Beenken A., Eliseenkova A. V., Meech R., Tsau C., et al. (2009). Differential interactions of FGFs with heparan sulfate control gradient formation and branching morphogenesis. PubMed DOI PMC

Makarenkova H. P., Ito M., Govindarajan V., Faber S. C., Sun L., McMahon G., et al. (2000). FGF10 is an inducer and Pax6 a competence factor for lacrimal gland development. PubMed

May A. J., Chatzeli L., Proctor G. B., Tucker A. S. (2015). Salivary gland dysplasia in Fgf10 heterozygous mice: a new mouse model of xerostomia. PubMed DOI PMC

May A. J., Headon D., Rice D. P., Noble A., Tucker A. S. (2016). FGF and EDA pathways control initiation and branching of distinct subsets of developing nasal glands. PubMed DOI PMC

Milunsky J. M., Zhao G., Maher T. A., Colby R., Everman D. B. (2006). LADD syndrome is caused by FGF10 mutations. PubMed DOI

Nakao Y., Mitsuyasu T., Kawano S., Nakamura N., Kanda S., Nakamura S. (2013). Fibroblast growth factors 7 and 10 are involved in ameloblastoma proliferation via the mitogen-activated protein kinase pathway. PubMed DOI PMC

Oginuma M., Moncuquet P., Xiong F., Karoly E., Chal J., Guevorkian K., et al. (2017). A gradient of glycolytic activity coordinates FGF and Wnt signaling during elongation of the body axis in amniote embryos. PubMed DOI PMC

Ohuchi H., Hori Y., Yamasaki M., Harada H., Sekine K., Kato S., et al. (2000). FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development. PubMed DOI

Ornitz D. M., Itoh N. (2001). Fibroblast growth factors. PubMed DOI PMC

Ornitz D. M., Itoh N. (2015). The fibroblast growth factor signaling pathway. PubMed DOI PMC

Patel V. N., Knox S. M., Likar K. M., Lathrop C. A., Hossain R., Eftekhari S., et al. (2007). Heparanase cleavage of perlecan heparan sulfate modulates FGF10 activity during ex vivo submandibular gland branching morphogenesis. PubMed DOI

Pauley S., Wright T. J., Pirvola U., Ornitz D., Beisel K., Fritzsch B. (2003). Expression and function of FGF10 in mammalian inner ear development. PubMed DOI PMC

Petersen C. I., Jheon A. H., Mostowfi P., Charles C., Ching S., Thirumangalathu S., et al. (2011). FGF signaling regulates the number of posterior taste papillae by controlling progenitor field size. PubMed DOI PMC

Pirvola U., Spencer-Dene B., Xing-Qun L., Kettunen P., Thesleff I., Fritzsch B., et al. (2000). FGF/FGFR-2(IIIb) signaling is essential for inner ear morphogenesis. PubMed DOI PMC

Prochazka J., Prochazkova M., Du W., Spoutil F., Tureckova J., Hoch R., et al. (2015). Migration of founder epithelial cells drives proper molar tooth positioning and morphogenesis. PubMed DOI PMC

Prochazkova M., Häkkinen T. J., Prochazka J., Spoutil F., Jheon A. H., Ahn Y., et al. (2017). FGF signaling refines Wnt gradients to regulate the patterning of taste papillae. PubMed DOI PMC

Qu X., Carbe C., Tao C., Powers A., Lawrence R., van Kuppevelt T. H., et al. (2011). Lacrimal gland development and Fgf10-Fgfr2b signaling are controlled by 2-O- and 6-O-sulfated heparan sulfate. PubMed DOI PMC

Rebustini I. T., Hoffman M. P. (2009). ECM and FGF-dependent assay of embryonic SMG epithelial morphogenesis: investigating growth factor/matrix regulation of gene expression during submandibular gland development. PubMed DOI PMC

Rice R., Spencer-Dene B., Connor E. C., Gritli-Linde A., McMahon A. P., Dickson C., et al. (2004). Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate. PubMed DOI PMC

Rohmann E., Brunner H. G., Kayserili H., Uyguner O., Nürnberg G., Lew E. D., et al. (2006). Mutations in different components of FGF signaling in LADD syndrome. PubMed DOI

Rosenquist T. A., Martin G. R. (1996). Fibroblast growth factor signalling in the hair growth cycle: expression of the fibroblast growth factor receptor and ligand genes in the murine hair follicle. PubMed DOI

Rothova M., Thompson H., Lickert H., Tucker A. S. (2012). Lineage tracing of the endoderm during oral development. PubMed DOI

Scheckenbach K., Balz V., Wagenmann M., Hoffmann T. K. (2008). An intronic alteration of the fibroblast growth factor 10 gene causing ALSG-(aplasia of lacrimal and salivary glands) syndrome. PubMed DOI PMC

Schell U., Hehr A., Feldman G. J., Robin N. H., Zackai E. H., de Die-Smulders C., et al. (1995). Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. PubMed DOI

Seymen F., Koruyucu M., Toptanci I. R., Balsak S., Dedeoglu S., Celepkolu T., et al. (2017). Novel FGF10 mutation in autosomal dominant aplasia of lacrimal and salivary glands. PubMed DOI

Shams I., Rohmann E., Eswarakumar V. P., Lew E. D., Yuzawa S., Wollnik B., et al. (2007). Lacrimo-auriculo-dento-digital syndrome is caused by reduced activity of the fibroblast growth factor 10 (FGF10)-FGF receptor 2 signaling pathway. PubMed DOI PMC

Shi M., Mostowska A., Jugessur A., Johnson M. K., Mansilla M. A., Christensen K., et al. (2009). Identification of microdeletions in candidate genes for cleft lip and/or palate. PubMed DOI PMC

Song Z., Liu C., Iwata J., Gu S., Suzuki A., Sun C., et al. (2013). Mice with Tak1 deficiency in neural crest lineage exhibit cleft palate associated with abnormal tongue development. PubMed DOI PMC

Sugii H., Grimaldi A., Li J., Parada C., Vu-Ho T., Feng J., et al. (2017). The Dlx5-FGF10 signaling cascade controls cranial neural crest and myoblast interaction during oropharyngeal patterning and development. PubMed DOI PMC

Tao H., Shimizu M., Kusumoto R., Ono K., Noji S., Ohuchi H. (2005). A dual role of FGF10 in proliferation and coordinated migration of epithelial leading edge cells during mouse eyelid development. PubMed DOI

Terao F., Takahashi I., Mitani H., Haruyama N., Sasano Y., Suzuki O., et al. (2011). Fibroblast growth factor 10 regulates Meckel’s cartilage formation during early mandibular morphogenesis in rats. PubMed DOI

Teshima T. H. N., Lourenco S. V., Tucker A. S. (2016). Multiple cranial organ defects after conditionally knocking out Fgf10 in the neural crest. PubMed DOI PMC

Urness L. D., Wang X., Shibata S., Ohyama T., Mansour S. L. (2015). Fgf10 is required for specification of non-sensory regions of the cochlear epithelium. PubMed DOI PMC

Veistinen L., Aberg T., Rice D. P. C. (2009). Convergent signalling through Fgfr2 regulates divergent craniofacial morphogenesis. PubMed DOI

Walker K. A., Sims-Lucas S., Bates C. M. (2016). Fibroblast growth factor receptor signaling in kidney and lower urinary tract development. PubMed DOI PMC

Wright T. J. (2003). Fgf3 and Fgf10 are required for mouse otic placode induction. PubMed DOI

Xu X., Weinstein M., Li C., Naski M., Cohen R. I., Ornitz D. M., et al. (1998). Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. PubMed

Yokohama-Tamaki T., Ohshima H., Fujiwara N., Takada Y., Ichimori Y., Wakisaka S., et al. (2006). Cessation of Fgf10 signaling, resulting in a defective dental epithelial stem cell compartment, leads to the transition from crown to root formation. PubMed DOI

Young N. M., Wat S., Diewert V. M., Browder L. W., Hallgrímsson B. (2007). Comparative morphometrics of embryonic facial morphogenesis: implications for cleft-lip etiology. PubMed DOI

Yu Y., Zuo X., He M., Gao J., Fu Y., Qin C., et al. (2017). Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity. PubMed DOI PMC

Zhang X., Ibrahimi O. A., Olsen S. K., Umemori H., Mohammadi M., Ornitz D. M. (2006). Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. PubMed DOI PMC