Disease relevance of Fgfr3

• We have generated the first mouse model of fibro-blast growth factor receptor 3 (Fgfr3) with the K644E mutation, which accurately reflects the embryonic onset of a neonatal lethal dwarfism, thanatophoric dysplasia type II (TDII) [1].
• Fibroblast growth factor receptor 3 (FGFR3) is a key regulator of skeletal growth and activating mutations in Fgfr3 cause achondroplasia, the most common genetic form of dwarfism in humans [2].
• Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers [3].
• FGFR3 expression was reduced in growth plates from T(3) receptor alpha-null mice, which exhibit skeletal hypothyroidism, but was increased in T(3) receptor beta(PV/PV) mice, which display skeletal thyrotoxicosis [4].
• Using a rat model of closed femoral fracture healing, we analyzed the spatial and temporal expression of FGFR3 [5].

Psychiatry related information on Fgfr3

• We also mapped the fibroblast growth factor receptor 3 (Fgfr3) gene, a potential candidate for tlt, and the Huntington's disease homolog (Hdh) gene to D5Mit268, approximately 4.3 centiMorgans (cM) from the tilted locus [6].

High impact information on Fgfr3

• Fibroblast growth factor receptor 3 (Fgfr3) is a tyrosine kinase receptor expressed in developing bone, cochlea, brain and spinal cord [7].
• Here we show that mice homozygous for a targeted disruption of Fgfr3 exhibit skeletal and inner ear defects [7].
• Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia [8].
• Fibroblast growth factor receptor 3 is a negative regulator of bone growth [9].
• Interestingly, these disorders display a graded spectrum of phenotypic severity and are the result of distinct missense mutations in the fibroblast growth factor receptor 3 gene (FGFR3) [8].

Chemical compound and disease context of Fgfr3

• Several gain-of-function mutations in a receptor tyrosine kinase, fibroblast growth factor receptor 3 (FGFR3), cause dwarfism in humans [10].
• A mouse model for achondroplasia was generated by introducing the human mutation (glycine 380-arginine) into the mouse fibroblast growth factor receptor 3 (G374R) by a "knock-in" approach using gene targeting leading to a constitutively active receptor [11].

Biological context of Fgfr3

• This role contrasts with the negative role of Fgfr3, although recent reports implicate FGF18, a ligand for FGFR3IIIc and FGFR2IIIc, as a co-ordinator of osteogenesis via these two receptors [12].
• This study excludes both Fgfr3 and Hdh as candidate genes for tlt and identifies closely linked microsatellite markers that will be useful for the positional cloning of tlt [6].
• However, mice doubly homozygous for disruptions of the fgfr-3 and fgfr-4 genes display novel phenotypes not present in either single mutant, which include pronounced dwarfism and lung abnormalities [13].
• The data show that osteoblasts derived from Stat1-/- mice have decreased expression of cell cycle inhibitor p21WAF/CIP and FGF receptor 3, a known negative regulator of chondrocyte proliferation [14].
• Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis [15].

Anatomical context of Fgfr3

• This suggests that signaling through Fgfr3 both promotes and inhibits chondrocyte proliferation, depending on the time during development [1].
• Using a novel micro-mechanical indentation protocol, it was shown that articular cartilage in the humeral head of 4-month-old Fgfr3(-/-) mice was less resistant to compressive force and less stiff than that of littermate controls [16].
• Additionally, Fgfr3 may coordinate the growth and differentiation of chondrocytes with the growth and differentiation of osteoprogenitor cells by simultaneously modulating Bmp4 and patched expression in both growth plate cartilage and in the perichondrium [2].
• Here we investigated the L5 spinal ganglion and the sciatic nerve of intact Fgfr3-deficient mice after nerve injury [17].
• Quantification of sensory neurons in the L5 spinal ganglion revealed no significant differences between wild-type and Fgfr3-deficient mice [17].

Associations of Fgfr3 with chemical compounds

• Fibroblast growth factor (FGF)-2 and FGF receptor 3 are required for the development of the substantia nigra, and FGF-2 plays a crucial role for the rescue of dopaminergic neurons after 6-hydroxydopamine lesion [18].
• Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation [19].
• The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3 [20].
• In conclusion FGF9 presents a unique case of ligand-receptor specificity and fulfills the criteria as a high affinity, heparin-dependent ligand for FGFR3 [21].
• In contrast, B9 cells overexpressing FGFR3 were resistant to treatment with dexamethasone, a phenomenon successfully reversed using a Bcl-x(L) antisense oligonucleotide [22].

Regulatory relationships of Fgfr3

• Conversely, Bmp4 expression is upregulated in the perichondrium of Fgfr3-/- mice [2].
• A Ser(365)-->Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia [23].
• To test this hypothesis, FGFR1 signaling was activated in the growth plate in cells that normally express FGFR3 [24].
• Here we show that targeted overexpression of CNP in chondrocytes counteracts dwarfism in a mouse model of achondroplasia with activated fibroblast growth factor receptor 3 (FGFR-3) in the cartilage [25].
• These studies support a dominant role for PTHrP in regulating the pool of proliferating cells during limb development and suggest that signalling by FGFR3 plays a more prominent role in cartilage maturation and vascular invasion at the chondro-osseous junction [26].

Other interactions of Fgfr3

• These data suggest that FGF18 acts as a physiological ligand for FGFR3 [27].
• Like FGFR1 and FGFR3, it exists as two splice variants, IIIb and IIIc [12].
• FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung [13].
• Fgfr3 expression is in contact with the Fgf8 expression domain only in the rostroventral hindbrain [28].
• Immunolocalization of FGFR2 and FGFR3 revealed overlap with Dach1 expression during skeletal patterning and chondrocyte maturation [29].

Analytical, diagnostic and therapeutic context of Fgfr3

• In the present study, we used in situ hybridization analysis to show that FGFR3 also has a unique pattern of expression during organogenesis [15].
• To assess a possible role for FGFR3 during healing, we also analyzed the spatial and temporal expression of signal transducer and activator of transcription-1 (STAT1) and cyclin-dependent kinase inhibitor p21, important mediators of FGFR3 signaling [5].
• Using this exon as a probe for mouse RNA as well as PCR analysis, demonstrated that exon IIIb encodes an authentic form of FGFR3 that is expressed in mouse embryo, mouse skin and mouse epidermal keratinocytes [30].
• Genomic organization of the human fibroblast growth factor receptor 3 (FGFR3) gene and comparative sequence analysis with the mouse Fgfr3 gene [31].
• Using gene targeting, we demonstrated that Fgfr3 plays an essential role in endochondral ossification and that a loss-of-function mutation causes accelerated and prolonged long bone growth [32].

References