Disease relevance of Fgf8

• Increased expression of fibroblast growth factor 8 in human breast cancer [1].
• By contrast, Bmpr1a mutant mice displayed decreased apoptosis and augmented Fgf8 expression in the DUE associated with GT hyperplasia [2].
• Fgf8 is activated by mouse mammary tumor virus insertion (MMTV) mutations at ~10% frequency in normal mice and at ~50% frequency in MMTV/Wnt-1 transgenic mice [3].
• MMTV/Fgf8 transgenic mice develop mammary and salivary gland neoplasias and ovarian stromal hyperplasia [4].
• Loss of Bmp7 and Fgf8 signaling in Hoxa13-mutant mice causes hypospadia [5].
• Furthermore, nonlinear effects of Fgf8 gene dose on the expression of a subset of genes, including Bmp4 and Msx1, correlate with a holoprosencephaly phenotype and with the nonlinear expression of transcription factors that regulate neocortical patterning [6].
• The androgen-inducible expression of Fgf8 in Shionogi Carcinoma 115, a mouse mammary tumor, controls this tumor's androgen-dependent phenotype [7], thus stimulating interest in this gene as a possible factor in human prostate cancer and other androgen-sensitive cancers [8] ; however, a study in the mouse found that the androgen regulation of Fgf8 1) could only be demonstrated in Shionogi Carcinoma 115-derived cells and not in other mouse mammary cell lines or in mouse prostate and 2) correlated with a tumor-specific translocation of Fgf8 to a DNA region containing androgen-regulated genes, thus suggesting that mouse Fgf8 is not inherently regulated by androgens [8].

Psychiatry related information on Fgf8

• To study the role of fibroblast growth factor 8 (FGF-8) in human development and malignancies, we have isolated and characterized its gene [9].

High impact information on Fgf8

• We report here that inactivating Fgf8 in early limb ectoderm causes a substantial reduction in limb-bud size, a delay in Shh expression, misregulation of Fgf4 expression, and hypoplasia or aplasia of specific skeletal elements [10].
• Lack of Fgf8 in the apical ectodermal ridge (AER) alters expression of other Fgf genes, Shh and Bmp2 [11].
• Here we report that conditional disruption of Fgf8 in the forelimb of developing mice bypasses embryonic lethality and reveals a requirement for Fgf8 in the formation of the stylopod, anterior zeugopod and autopod [11].
• The expression pattern and activity of fibroblast growth factor-8 (FGF8) in experimental assays indicate that it has important roles in limb development, but early embryonic lethality resulting from mutation of Fgf8 in the germ line of mice has prevented direct assessment of these roles [11].
• We provide evidence that intersections of Shh, which is expressed along the ventral neural tube, and FGF8, which is locally produced at the mid/hindbrain boundary and in the rostral forebrain, create induction sites for dopaminergic neurons in the midbrain and forebrain [12].

Chemical compound and disease context of Fgf8

• In addition, the heparin-binding growth factor fraction of Shionogi 115 (S115) mouse breast cancer cells, which express and secrete FGF-8 at a very high level, had an effect in bone marrow cultures similar to that of exogenous FGF-8 [13].

Biological context of Fgf8

• We have analyzed the phenotype of Fgf8(-/-) embryos and discovered that they fail to express Fgf4 in the streak [14].
• Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo [14].
• 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 [15].
• Our data show that Fgf8 is part of a complex gene regulatory network that is essential for cell survival in the mes/met [16].
• Urethral signaling regions, as indicated by Shh and Fgf8 expression, are established in Fgfr2-IIIb null mice; however, cell proliferation arrests prematurely and maturation of the urethral epithelium is disrupted [17].

Anatomical context of Fgf8

• In the mouse, Fgf8 is also expressed in endoderm as well as in other germ layers in the periotic placode region [18].
• Fgf8 and Fgf4 encode FGF family members that are coexpressed in the primitive streak of the gastrulating mouse embryo [14].
• 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 [19].
• Fgf8, which is expressed at the embryonic mid/hindbrain junction, is required for and sufficient to induce the formation of midbrain and cerebellar structures [20].
• We found that Fgf8 mutation increases the severity of the primary defect caused by Tbx1 haploinsufficiency, i.e. early hypoplasia of the fourth pharyngeal arch arteries, consistent with the time and location of the shared expression domain of the two genes [21].

Associations of Fgf8 with chemical compounds

• Upon synthesis under the control of androgen, AIGF is immediately secreted into the extracellular space without intracellular accumulation [22].
• The biological ability of AIGF to stimulate SC-3 cell growth is inhibited by heparin or suramin [22].
• In addition, treatment of SC-3 cells with sulfation blocker (chlorate) or heparitinase results in the abolishment of their ability to respond to androgen or AIGF, indicating that heparan sulfate has important roles for condensing AIGF on or near the cell surface as well as potentiating the biological activity of AIGF [22].
• FGF8 mRNA was expressed in DMSO-treated embryonic stem (ES) cells [23].
• Substitution of Tyr-58 or Glu-132 or Leu-179 of the FGF8 with alanine reduced the binding affinity, while substitution of Tyr-139 with alanine did not alter the binding affinity [24].

Physical interactions of Fgf8

• To address the possibility that the FGF-8 isoforms might interact with different fibroblast growth factor receptors, we prepared recombinant FGF-8 protein isoforms [25].
• Deletion of Fgf8 or inhibition of binding between Fgf8 and Fgfr3 leads to defects in PC development, whereas overexpression of Fgf8 or exogenous Fgfr3 activation induces ectopic PC formation and inhibits OHC development [26].

Co-localisations of Fgf8

• We demonstrate that Fgf8 expression in wild type limbs colocalizes spatially and temporally with AER cell death in Dac limbs [27].

Regulatory relationships of Fgf8

• FGF8 can activate Gbx2 and transform regions of the rostral mouse brain into a hindbrain fate [28].
• However, in the absence of Gbx2, FGF8 can nevertheless repress Otx2 expression in midbrain explants [20].
• Taken together, our results indicate that Lmx1b plays an essential role in the development of the tectum and cerebellum by regulating expression of Fgf8, Wnt1 and several isthmus-related transcription factors in the MHB, and is a crucial component of a cross-regulatory network required for the induction activity of the isthmic organizer in the MHB [29].
• These results indicate that, like BMP4, FGF8 constitutes an epithelial inductive signal capable of inducing the expression of downstream signaling molecules in dental mesenchyme via Msx1 [30].
• Wnt-1 regulates Fgf8 expression in the adjacent metencephalon, most likely via a secondary mesencephalic signal [31].

Other interactions of Fgf8

• We show that maintenance of Shh expression in the posterior mesenchyme is not dependent on either expression of Fgf4 or normal levels of Fgf8 in the overlying AER [32].
• In the diencephalon of the mutant, Bmp4 expression is maintained, whereas Fgf8 expression is not detectable [33].
• FGF8 and WNT1 have been implicated as key components of IsO signaling activity, and previous studies have shown that in Wnt1(-/-) embryos, the mes/met is deleted by the 30 somite stage ( approximately E10) (McMahon, A. P. and Bradley, A. (1990) Cell 62, 1073-1085) [16].
• Also the reciprocal regulatory loop proposed for Fgf8 in the AER and Fgf10 in the underlying mesenchyme is also uncoupled by this mutation [32].
• Embryos deficient for both OTX2 and GBX2 proteins (hOtx1(2)/hOtx1(2); Gbx2(-/-)) show abnormal patterning of the anterior neural tissue, which is evident at the presomite-early somite stage prior to the onset of Fgf8 neuroectodermal expression [34].

Analytical, diagnostic and therapeutic context of Fgf8

• In situ hybridization of breast cancer tissues and analysis of purified populations of normal epithelial cells and breast cancer cell lines showed that malignant epithelial cells expressed FGF8 mRNA at high levels compared to non-malignant epithelial and myoepithelial cells and fibroblasts [1].
• Southern blotting did not detect MMTV insertions near Fgf8 but did reveal a specific DNA rearrangement 3.7 kb upstream of Fgf8 in S115 cells and in other cells (SC115) independently derived from Shionogi carcinoma 115 [8].
• Spectral karyotyping of S115 cells and sequencing of the cloned rearrangement junctions indicate that Fgf8 is involved in a t(5;19) translocation [8].
• Sequence analysis of Fgf8 and Chuk1, which are localized close to the marker D19Mit10, detected no mutations in the ak/ak mutants [35].
• FGF-3, FGF-4, and FGF-8 were not detectable by RT-PCR in either proliferating or differentiated skeletal muscle cells [36].

References