Disease relevance of FGF8

• Furthermore, continuous and widespread misexpression of FGF-8 causes limb truncations and skeletal alterations with phocomelic or achondroplasia phenotype [1].

High impact information on FGF8

• Here, we show that three WNT factors signaling through beta-catenin act as key regulators of the FGF-8/FGF-10 loop [2].
• FGF8 secreted by the ectoderm then appears to initiate limb bud formation by promoting outgrowth of and Sonic hedgehog expression in the underlying lateral plate mesoderm [3].
• FGF8 also maintains mesoderm outgrowth and Sonic hedgehog expression in the established limb bud [3].
• We provide evidence that FGF8 serves as an endogenous inducer of chick limb formation and that its expression in the intermediate mesoderm at the appropriate time and place to trigger forelimb development is directly linked to the mechanism of embryonic kidney differentiation [3].
• One function of the limb inducer is to initiate Fgf8 gene expression in the ectoderm overlying the prospective limb-forming territories [3].

Biological context of FGF8

• The mandibular processes are specified as at least two independent functional regions: two large lateral regions where morphogenesis is dependent on fibroblast growth factor (FGF)-8 signaling, and a small medial region where morphogenesis is independent of FGF-8 signaling [4].
• These functional studies, together with our tissue distribution studies, suggest that FGF-mediated signaling (other than FGF-8), through interactions with FGF receptor-2 and downstream target genes including Msx genes, is part of the signaling pathway that mediates the growth-promoting interactions in the medial region of the developing mandible [4].
• Rather, these malformations result from loss of fibroblast growth factor 8 and sonic hedgehog expression, which leads to increased programmed cell death and decreased proliferation in the forebrain and frontonasal process [5].
• It is of great interest to uncover mechanisms of signal transduction pathways downstream of the Fgf8 signal in tectal and cerebellar development, and in this report we have concentrated on the Ras-ERK pathway [6].
• We find that SHH and FGF8 have strong synergistic effects on chondrogenesis in vitro and are sufficient to promote outgrowth and chondrogenesis in vivo, suggesting a very specific role for these molecules in producing the elongated beak structures during chick facial development [7].

Anatomical context of FGF8

• Otx2, Gbx2, and Fgf8 expression patterns in the chick developing inner ear and their possible roles in otic specification and early innervation [8].
• Our results also suggest that the maculae of the saccule and lagena, and the medial portion of the macula utriculi could arise within a broad Fgf8-positive domain previously observed at the otocyst stage [8].
• The relationship between Gbx2 and Fgf8 expression changed during inner ear development but was always related to the macula sacculi innervation and endolymphatic duct formation [8].
• Our data thus point to FGF8 as a key regulator of limb development that not only induces and initiates the formation of a limb bud, but also sustains its subsequent development [3].
• These presumably result from step-like isthmic organizer effects on Otx2-expressing midbrain neuroepithelium at different distances from a caudal FGF8 morphogen source (isthmic Fgf8-positive domain) [9].

Associations of FGF8 with chemical compounds

• Local retinoid signaling coordinates forebrain and facial morphogenesis by maintaining FGF8 and SHH [5].
• Different combinations of signals are responsible for different aspects of this early transient induction: FGF initiates expression of Sox3 and ERNI, retinoic acid can induce Cyp26A1 and only a combination of low levels of FGF8 together with Wnt- and BMP-antagonists can induce Otx2 [10].
• Exogenous implantation of Fgf4 in normal, aneural, and muscleless limbs induces scleraxis and tenascin expression but not that of Fgf8 [11].

Regulatory relationships of FGF8

• Moreover, BMP4 is downstream to Activin signals and controls Fgf8 [12].

Other interactions of FGF8

• The growth factor IGF-I produced by the intermediary mesoderm or mesonephros (embryonary kidney) could be implicated in the induction limb development and the application of FGF-8 protein to the flank of young chick embryos inducing the development of additional limbs [13].
• A Wnt/beta-catenin pathway controls Nodal expression in and around Hensen's node, without affecting the upstream regulators Sonic hedgehog, Car and Fibroblast Growth Factor 8 [14].

Analytical, diagnostic and therapeutic context of FGF8

• Using in ovo electroporation of PSM cells, we demonstrate that constitutive activation of ERK signaling in the PSM blocks segmentation by preventing maturation of PSM cells, thus phenocopying the overexpression of FGF8 [15].
• Fibroblast growth factor-8 expression, however, was unaltered 30 h after treatment but was greatly reduced at 48 h post-treatment, when the AER begins to regress [16].
• Denervation prevented Fgf8 and 10 upregulation, suggesting Fgf pathways are downstream of nerve-dependence [17].
• RT-PCR analysis indicates that chick Fgf8, like its mouse and human counterpart is alternatively spliced [18].

References