Disease relevance of Fgf10

• Defective growth in the anterior palate of Msx1-/- and Fgf10-/- mice leads to a complete cleft palate and supports the anterior-to-posterior direction of palatal closure [1].
• Congenital heart defects in Fgfr2-IIIb and Fgf10 mutant mice [2].
• Fgfr2-IIIb and Fgf10 mutant mice provide new models for common components of congenital heart disease [2].
• FGF-10 deficient mutant male mouse revealed normal corporal bodies with failure of the urethral plate to fuse ventrally consistent with hypospadias [3].
• A survey of primary human breast carcinomas revealed strongly elevated Fgf10 mRNA levels in approximately 10% of the tumors tested, suggesting that Fgf10 may also be involved in oncogenicity of a subset of human breast cancers [4].
• Our observations indicate that stromal FGF10 expression may facilitate the multifocal histology observed in prostate adenocarcinoma and suggest the FGF10/FGFR1 axis as a potential therapeutic target in treating hormone-sensitive or refractory prostate cancer [5].

High impact information on Fgf10

• Fgf10(+/-) mice have a phenotype similar to ALSG, providing a model for this disorder [6].
• Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands [6].
• FGF7 and FGF10, the closest relatives of FGF22, share this activity; other FGFs have distinct effects [7].
• In Fgf10-/- embryos, limb bud formation was initiated but outgrowth of the limb buds did not occur; however, formation of the clavicles was not affected [8].
• In mouse, mesodermal Fgf10 acting redundantly with neural Fgf3 is required for induction of the placode [9].

Chemical compound and disease context of Fgf10

• Efficacy of keratinocyte growth factor-2 in dextran sulfate sodium-induced murine colitis [10].

Biological context of Fgf10

• Mice lacking either component (Fgfr2b-/- or Fgf10-/-) were examined to determine the role of Fgfr2b-mediated signaling during gastric organogenesis [11].
• METHODS: Stomachs from embryonic day 13.5-18.5 Fgfr2b-/-, Fgf10-/-, and wild-type littermates were collected and analyzed by conventional histology, immunohistochemistry, in situ hybridization, and electron microscopy [11].
• In mouse, the fibroblast growth factors Fgf8, Fgf10 and Fgf18 are thought to affect multiple processes of pituitary development: morphogenesis and patterning of the adenohypophyseal anlage; and survival, proliferation and differential specification of adenohypophyseal progenitor cells [12].
• To elucidate the roles of FGF10 during eyelid formation, we examined the expression pattern of Fgf10 during eyelid formation and the phenotype of Fgf10-null eyelids in detail [13].
• Regulation of mesenchymal Fgf10 gene expression by the epithelial Shh was indicated during late GT development [14].

Anatomical context of Fgf10

• The signaling pathways between endoderm-derived gastric epithelium and the surrounding mesenchyme are largely unknown; however, the developmental expression profile of the IIIb isoform of Fgfr2 (Fgfr2b) and its main ligand, Fgf10, suggest that they may be strong candidates [11].
• However, Fgf10-null epithelial cells running though the eyelid groove do not exhibit typical cuboid shape or sufficient proliferation [13].
• Fibroblast growth factors (FGFs) often mediate epithelial-mesenchymal interactions and mesenchymal Fgf10 is essential for epithelial branching in the developing lung [15].
• In contrast, despite its vital role during limb-bud formation, Fgf10 appears not to be primarily essential for initial outgrowth of GT, as extrapolated from Fgf10(-/-) GTs [16].
• The temporal and spatial pattern of gene expression suggests that Fgf10 plays a role in directional outgrowth and possibly induction of epithelial buds, and that positive and negative regulators of Fgf10 are produced by the endoderm [17].

Associations of Fgf10 with chemical compounds

• We show that altering endogenous gradients of HS sulfation with sodium chlorate or over-O-sulfated synthetic heparin in lung organ cultures dramatically decreases Fgf10 binding [18].
• The mitogenic activity of FGF-10 could be distinguished from that of KGF by its different sensitivity to heparin and lack of neutralization by a KGF monoclonal antibody [19].
• Retinoic acid selectively regulates Fgf10 expression and maintains cell identity in the prospective lung field of the developing foregut [20].
• In cultures of UGS, the FGF-10 null phenotype was partially reversed by the addition of FGF-10 and testosterone, resulting in the formation of prostatic buds [21].
• Herein, we demonstrate that FGF10 stimulation of mouse lung epithelial cells (MLE15) overexpressing mSpry2 results in both mSpry2 tyrosine phosphorylation and differential binding of mSpry2 to several key upstream target proteins in the MAP kinase-activating pathway [22].

Enzymatic interactions of Fgf10

• The failure of exogenous FGF10 to phosphorylate its known downstream targets ERK and AKT in lung mesenchymal cultures strongly suggests that FGF10 acts indirectly on the progenitor population via an epithelial intermediate [23].

Regulatory relationships of Fgf10

• Proximal-to-distal growth of the embryonic limbs requires Fgf10 in the mesenchyme to activate Fgf8 in the apical ectodermal ridge (AER), which in turn promotes mesenchymal outgrowth [24].
• Tbx5 directly activates the Fgf10 gene via a conserved binding site, providing a simple and direct mechanism for limb bud initiation [25].
• Tracheal epithelium treated with FGF10 showed little growth and failed to express SP-C as measured by whole-mount in situ hybridization and quantitative real-time polymerase chain reaction [26].
• We find that, as expected, Bmp4 can suppress bud extension in isolated epithelium stimulated by Fgf10, but interestingly, Bmp7 has no discernible effect [27].
• Our results demonstrate that mesenchymal Fgf10 regulates the epithelial expression of Shh, which in turn signals back to the mesenchyme [28].

Other interactions of Fgf10

• Glands cultured with SU5402 were then rescued with exogenous BMP7, FGF7 or FGF10 [29].
• Also the reciprocal regulatory loop proposed for Fgf8 in the AER and Fgf10 in the underlying mesenchyme is also uncoupled by this mutation [30].
• Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction [31].
• The reduction in the amount of mesenchyme in Fgf9(-/-) lungs limits expression of mesenchymal Fgf10 [15].
• In the absence of Tbx5, the FGF and Wnt regulatory loops required for limb bud outgrowth are not established, including initiation of Fgf10 expression [25].

Analytical, diagnostic and therapeutic context of Fgf10

• Experiments in intact lung organ cultures demonstrate that Fgf10 is a chemotactic factor for distal, but not for proximal, epithelium [18].
• Fgf10-null whiskers exhibit a significant decrease in number and their structure is disorganized as revealed by scanning electron microscopy [32].
• In situ hybridization analysis showed developmentally regulated expression during tooth formation for Fgf-3 and Fgf-10 that was mainly restricted to the dental papilla mesenchymal cells [33].
• To test whether FGF10 deficiency is an underlying cause of the Gas1 mutant phenotype, we employed a limb culture system in conjunction with microinjection of recombinant proteins [24].
• We suggest a model whereby FGF9 signaling from the epithelium and reciprocal FGF10 signaling from the mesenchyme coordinately regulate epithelial airway branching and organ size during lung embryogenesis [15].

References