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Highly Accessed Protein family review

Fibroblast growth factors

David M Ornitz1* and Nobuyuki Itoh2

Author affiliations

1 Department of Molecular Biology and Pharmacology, Washington University Medical School, 660 S. Euclid Avenue, St. Louis, MO 63110, USA

2 Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Yoshida-Shimoadachi, Sakyo, Kyoto 606-8501, Japan

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Citation and License

Genome Biology 2001, 2:reviews3005-reviews3005.12  doi:10.1186/gb-2001-2-3-reviews3005


The electronic version of this article is the complete one and can be found online at: http://genomebiology.com/2001/2/3/reviews/3005


Published:9 March 2001

© 2001 BioMed Central Ltd

Summary

Fibroblast growth factors (FGFs) make up a large family of polypeptide growth factors that are found in organisms ranging from nematodes to humans. In vertebrates, the 22 members of the FGF family range in molecular mass from 17 to 34 kDa and share 13-71% amino acid identity. Between vertebrate species, FGFs are highly conserved in both gene structure and amino-acid sequence. FGFs have a high affinity for heparan sulfate proteoglycans and require heparan sulfate to activate one of four cell-surface FGF receptors. During embryonic development, FGFs have diverse roles in regulating cell proliferation, migration and differentiation. In the adult organism, FGFs are homeostatic factors and function in tissue repair and response to injury. When inappropriately expressed, some FGFs can contribute to the pathogenesis of cancer. A subset of the FGF family, expressed in adult tissue, is important for neuronal signal transduction in the central and peripheral nervous systems.

Gene organization and evolutionary history

Gene organization

The prototypical Fgf genes contain three coding exons (Figure 1), with exon 1 containing the initiation methionine, but several Fgf genes (for example, Fgf2 and Fgf3) have additional 5' transcribed sequence that initiates from upstream CUG codons [1,2]. The size of the coding portion of Fgf genes ranges from under 5 kb (in Fgf3 and Fgf4) to over 100 kb (in Fgf12). In several Fgf subfamilies, exon 1 is subdivided into between two and four alternatively spliced sub-exons (denoted 1A-1D in the case of Fgf8). In these Fgf genes, a single initiation codon (ATG) in exon 1A is used. This gene organization is conserved in humans, mouse and zebrafish, but its functional consequences are poorly understood. Other subfamilies of Fgfs (such as Fgf11-14) have alternative amino termini, which result from the use of alternative 5' exons. It is not known whether a common 5' untranslated exon splices to these exons or whether alternative promoter and regulatory sequences are used.

thumbnailFigure 1. Gene structure of selected members of the Fgf family. Only the portion of each gene containing coding exons is shown. Constitutively expressed exons are in black; alternatively spliced exons are in gray. Fgfs1, 2, 4 and 9 contain the prototypic three-exon organization. For Fgf1, 5' untranslated exons are not shown; inclusion of these exons extends the gene by approximately 69 kb [78]. Fgf8 is an example of a gene with 5' alternative splicing, and Fgf13 demonstrates alternatively used 5' exons separated by over 30 kb. References: Fgf1 [78]; Fgf2 [79]; Fgf4 [80]; Fgf8 [52]; Fgf9 [81]; Fgf13 [76].

Most Fgf genes are found scattered throughout the genome. In human, 22 FGF genes have been identified and the chromosomal locations of all except FGF16 are known (Table 1) [3,4,5,6,7]. Several human FGF genes are clustered within the genome. FGF3, FGF4 and FGF19 are located on chromosome 11q13 and are separated by only 40 and 10 kb, respectively; FGF6 and FGF23 are located within 55 kb on chromosome 12p13; and FGF17 and FGF20 map to chromosome 8p21-p22. These gene locations indicate that the FGF gene family was generated both by gene and chromosomal duplication and translocation during evolution. Interestingly, a transcriptionally active portion of human FGF7, located on chromosome 15q13-q22, has been amplified to about 16 copies, which are dispersed throughout the human genome [8].

Table 1. Chromosomal localizations of FGFs in human and mouse

In the mouse, there are at least 22 Fgf genes [3,9], and the locations of 16 have been identified (Table 1). Many of the mouse Fgf genes are scattered throughout the genome, but as in the human, Fgf3, Fgf4 and Fgf19 are closely linked (within 80 kb on chromosome 7F) and Fgf6 and Fgf23 are closely linked on chromosome 6F3-G1.

Evolutionary history

Fgfs have been identified in both invertebrates and vertebrates [3]. Interestingly, an Fgf-like gene is also encoded in the nuclear polyhedrosis virus genome [10]. Fgf-like sequences have not been found in unicellular organisms such as Escherichia coli and Saccharomyces cerevisiae. Although the Drosophila and Caenorhabditis elegans genomes have been sequenced, only one Fgf gene (branchless) has been identified in Drosophila [11] and two (egl-17 and let-756) have been identified in C. elegans [12,13], in contrast to the large number of Fgf genes identified in vertebrates. The evolutionary relationship between invertebrate and vertebrate Fgfs is shown in Figure 2a.

thumbnailFigure 2. Evolutionary relationships within the FGF family. (a) Apparent evolutionary relationships between FGFs from vertebrates, invertebrates and a virus. Amino-acid sequences of nine representative FGFs were chosen from human and compared with FGFs from Drosophila, C. elegans, zebrafish and Autographa californica nuclear polyhedrosis virus. (b) Apparent evolutionary relationships of the 22 known human and murine FGFs. Sequences were aligned using Genetyxsequence analysis software and trees were constructed from the alignments using the neighbor-joining method.

The Fgf gene expansion has been hypothesized to be coincident with a phase of global gene duplications that took place during the period leading to the emergence of vertebrates [14]. Across species, most orthologous FGF proteins are highly conserved and share greater than 90% amino-acid sequence identity (except human FGF15 and mouse Fgf19; see below). To date, four Fgfs (Fgf3, 8, 17 and 18) have been identified in zebrafish, seven (Fgf3, Fgf(i), Fgf(ii), Fgf8, 9 and 20) in Xenopus (Fgf(i) and Fgf(ii) are most closely related to Fgf4 and Fgf6 [15]) and seven (Fgf2, 4, 8, 12, 14, 18 and 19) in chicken [3].

The apparent evolutionary relationships of the 22 known human FGFs are shown in Figure 2b. Vertebrate FGFs can be classified into several subgroups or subfamilies. Members of a subgroup of FGFs share increased sequence similarity and biochemical and developmental properties. For example, members of the FGF8 subfamily (FGF8, FGF17, and FGF18) have 70-80% amino acid sequence identity, similar receptor-binding properties and some overlapping sites of expression (for example, the midbrain-hindbrain junction) [16,17]. Members of FGF subgroups are not closely linked in the genome, however, indicating that the subfamilies were generated by gene-translocation or by genome-duplication events, not by local duplication events.

Human FGF15 and mouse Fgf19 have not been identified. Human FGF19 is evolutionarily most closely related to mouse Fgf15 (51% amino acid identity; Figure 2b) [18] and both the human FGF19 and mouse Fgf15 genes are closely linked to the human and mouse Fgf3 and Fgf4 genes on orthologous regions of human chromosome 11q13 and mouse chromosome 7F (N.I., unpublished observations). These findings indicate that human FGF19 may be the human ortholog of mouse Fgf15. Because all other Fgf orthologs share greater than 90% amino acid identity, it remains possible that the true orthologs of these genes have not been identified, have been lost or have diverged during vertebrate evolution.

Characteristic structural features

FGFs range in molecular weight from 17 to 34 kDa in vertebrates, whereas the Drosophila FGF is 84 kDa. Most FGFs share an internal core region of similarity, with 28 highly conserved and six identical amino-acid residues [19]. Ten of these highly conserved residues interact with the FGF receptor (FGFR) [20]. Structural studies on FGF1 and FGF2 identify 12 antiparallel β strands in the conserved core region of the protein (Figure 3) [21,22]. FGF1 and FGF2 have a β trefoil structure that contains four-stranded β sheets arranged in a triangular array (Figure 3b; reviewed in [23]). Two β strands (strands β10 and β11) contain several basic amino-acid residues that form the primary heparin-binding site on FGF2. Regions thought to be involved in receptor binding are distinct from regions that bind heparin (Figure 3) [21,22,23,24].

thumbnailFigure 3. (a) Structural features of the FGF polypeptide. The amino terminus of some FGFs contains a signal sequence (shaded). All FGFs contain a core region that contains conserved amino-acid residues and conserved structural motifs. The locations of β strands within the core region are numbered and shown as black boxes. The heparin-binding region (pink) includes residues in the loop between β strands 1 and 2 and in β strands 10 and 11. Residues that contact the FGFR are shown in green (the region contacting Ig-domain 2 of the receptor), blue (contacting Ig-domain 3) and red (contacting the alternatively spliced region of Ig-domain 3). Amino-acid residues that contact the linker region are shown in gray [20]. (b) Three-dimensional structure of FGF2, a prototypical member of the FGF family. A ribbon diagram of FGF2 is shown; β strands are labeled 1-12 and regions of contact with the FGFR and heparin are color-coded as in (a) [22,24]. Image provided by M. Mohammadi.

Localization and function

Localization

Subcellular localization and secretion

Most FGFs (FGFs 3-8, 10, 15, 17-19, and 21-23) have amino-terminal signal peptides and are readily secreted from cells. FGFs 9, 16 and 20 lack an obvious amino-terminal signal peptide but are nevertheless secreted [25,26,27]. FGF1 and FGF2 also lack signal sequences, but, unlike FGF9, are not secreted; they can, however, befound on the cell surface and within the extracellular matrix. FGF1 and FGF2 may be released from damaged cells or could be released by an exocytotic mechanism that is independent of the endoplasmic-reticulum-Golgi pathway [28]. FGF9 has been shown to contain a non-cleaved amino-terminal hydrophobic sequence that is required for secretion [29,30]. A third subset of FGFs (FGF11-14) lack signal sequences and are thought to remain intracellular [31,32,33,34]. It is not known whether these FGFs interact with known FGFRs or function in a receptor-independent manner within the cell. FGF2 and FGF3 have high-molecular-weight forms that arise from initiation from upstream CUG codons [2,14,35]. The additional amino-terminal sequence in these proteins contains nuclear-localization signals, and the proteins can be found in the nucleus; the biological function of nuclear-localized FGF is unclear.

Developmental expression patterns and function

The 22 members of the mammalian FGF family are differentially expressed in many, if not all, tissues, but the patterns and timing of expression vary. Subfamilies of FGFs tend to have similar patterns of expression, although each FGF also appears to have unique sites of expression. Some FGFs are expressed exclusively during embryonic development (for example, Fgf3, 4, 8, 15, 17 and 19), whereas others are expressed in embryonic and adult tissues (for example, Fgf1, 2, 5-7, 9-14, 16, 18, and 20-23).

Function

The expression patterns of FGFs (see above) suggest that they have important roles in development. FGFs often signal directionally and reciprocally across epithelial-mesenchymal boundaries [36]. The integrity of these signaling pathways requires extremely tight regulation of FGF activity and receptor specificity. For example, in vertebrate limb development, mesenchymally expressed Fgf10 in the lateral-plate mesoderm induces the formation of the overlying apical ectodermal ridge; the ridge subsequently expresses Fgf8, which signals back to the underlying mesoderm [37]. This directional signaling initiates feedback loops and, along with other signaling molecules, regulates the outgrowth and patterning of the limb. Importantly, the differential expression of the alternative splice forms of the receptors in the apical ectodermal ridge and underlying mesoderm is such as to limit or prevent autocrine signaling within a given compartment.

Studies of the biochemical activities of FGFs have focused on the specificity of interactions between FGFs and FGFRs, on factors that affect the stability of FGFs and on the composition and mechanism of the active FGF-FGFR signaling complex.

Specificity of FGFs for FGF receptors

The FGFR tyrosine kinase receptors contain two or three immunoglobulin-like domains and a heparin-binding sequence [38,39,40]. Alternative mRNA splicing of the FGFR gene specifies the sequence of the carboxy-terminal half of immunoglobulin-domain III, resulting in either the IIIb or the IIIc isoform of the FGFR [41,42,43]. This alternative-splicing event is regulated in a tissue-specific manner and dramatically affects ligand-receptor binding specificity [44,45,46,47,48]. Exon IIIb is expressed in epithelial lineages and exon IIIc tends to be expressed in mesenchymal lineages [44,46,47,48]. In vitro patterns of binding specificity have been determined for each splice form of FGFR1-3 and for FGFR4, which is not alternatively spliced [49,50,51]. Ligands specific for these receptor splice forms are expressed in adjacent tissues, resulting in directional epithelial-mesenchymal signaling. For example, epithelially expressed FGFR2b (that is, FGFR2 IIIb isoform) can be activated by FGF7 and FGF10, ligands produced in mesenchymal tissue [49,50,51]. These ligands show no activity towards mesenchymally expressed FGFR2c. Conversely, FGF8 is expressed in epithelial tissue and activates FGFR2c but shows no activity towards FGFR2b ([49,52] and our unpublished observations). Notably, FGF8 expression is often restricted to epithelial tissue such as the apical ectodermal ridge of the developing limb bud [53,54].

Interaction with heparin or heparan sulfate proteoglycans

An important feature of FGF biology involves the interaction between FGF and heparin or heparan sulfate (HS) proteoglycan (HSPG) [19]. These interactions stabilize FGFs to thermal denaturation and proteolysis and may severely limit their diffusion and release into interstitial spaces [55,56]. FGFs must saturate nearby HS-binding sites before exerting an effect on tissue further away, or else must be mobilized by heparin/HS-degrading enzymes. The interaction between FGFs and HS results in the formation of dimers and higher-order oligomers [57,58,59]. Although the biologically active form of FGF is poorly defined, it has been established that heparin is required for FGF to effectively activate the FGFR in cells that are deficient in or unable to synthesize HSPG or in cells pretreated with heparin/HS-degrading enzymes or inhibitors of sulfation [60,61,62]. Genetic studies have also shown that mutations in enzymes involved in HS biosynthesis affect FGF signaling pathways during development [19,63]. Additional studies have shown that heparin and/or HS act to increase the affinity and half-life of the FGF-FGFR complex (reviewed in [40,64]).

A minimal complex containing one FGF molecule per FGFR can form in the absence of HS [24]. Structural studies suggest that HS may bridge FGF2 and the FGFR by binding to a groove formed by the heparan-binding sites of both the ligand and the receptor [24,65]. Binding studies with soluble chimeric FGFRs have identified a second potential FGF-binding site that, in some cases, can interact cooperatively with the primary FGF-binding site [66].

Important mutants

Many members of the Fgf family have been disrupted by homologous recombination in mice. The phenotypes range from very early embryonic lethality to subtle phenotypes in adult mice. The major phenotypes observed in Fgf knockout mice are shown in Table 2. Because FGFs within a subfamily have similar receptor-binding properties and overlapping patterns of expression, functional redundancy is likely to occur. This has been demonstrated for Fgf17 and Fgf8, which cooperate to regulate neuroepithelial proliferation in the midbrain-hindbrain junction [17]. In the case of Fgf knockouts resulting in early lethality, other functions later in development will need to be addressed by constructing conditional alleles that can be targeted at specific times and places in development. For example, Fgf8-/- mice die by embryonic day 9.5 [67]. A conditional allele for Fgf8 targeted to the apical ectodermal ridge has been used to demonstrate an essential role for Fgf8 in early limb development [68,69].

Table 2. FGF knockout mice

Several mutations in Fgf genes have been identified in C. elegans, Drosophila, zebrafish, mouse and human. The C. elegans gene egl-17 is required for sex myoblast migration [12], and a null allele of let-756 causes developmental arrest of the early larva [13]. The Drosophila branchless gene is required for tracheal branching and cell migration [11]. In zebrafish, acerebellar (ace) embryos lack the cerebellum and the midbrain-hindbrain boundary organizer. The ace gene encodes the zebrafish homolog of Fgf8 [70]. Interestingly, zebrafish aussicht mutant embryos, which overexpress Fgf8, also have defects in development of the central nervous system [71].

In the mouse, the angora mutation, which affects hair growth, was found to be allelic with Fgf5 [72]. A mouse mutant with a Crouzon-syndrome-like craniofacial dysmorphology phenotype was found to result from an insertional mutation in the Fgf3/Fgf4 locus [73]. Recently, positional cloning of the autosomal dominant hypophosphataemic rickets gene identified missense mutations in human FGF23 [74]. A recent paper demonstrates that this disease is caused by a gain-of-function mutation [75]. The chromosomal location (Xq26) and tissue-specific expression pattern of Fgf13 (also called Fhf2) suggests that it may be a candidate gene for Borjeson-Forssman-Lehmann syndrome, an X-linked mental retardation syndrome [76].

Frontiers

Issues most studied

FGFs have been intensely studied for nearly 30 years. Most of the early work focused on the mechanisms that regulate stability, secretion, export and interactions with heparin and on the mechanisms and consequences of signal transduction in various types of cells. More recent work has focused on the mechanisms regulating receptor specificity and receptor activation, the structure of the FGF-FGFR-HS complex, and the identification of new members of the FGF family. Functional studies have begun to address the role of FGFs in cell biology, development and physiology. Initial studies focused on the regulation of cell proliferation, migration and differentiation; more recent work has addressed the negative effect of FGFs and FGFRs on proliferation of some cell types, which was surprising as FGFs were thought to promote proliferation. In vitro studies have now been complemented by gene targeting in mice. The knockout approach has been fairly successful in identifying primary phenotypes but will be challenged by the need to address redundancy amongst the 22 FGFs and to study their developmental and physiological functions after the point of lethality of the null allele.

Unresolved questions

A major unresolved question concerns the mechanism(s) regulating FGF activity in vivo in the presence of cell-surface and extracellular-matrix HSPG. Current hypotheses predict that tissue-specific heparan fragments of defined sequence (and particularly of defined sulfation pattern) will differentially regulate FGFs by controlling their diffusion in the extracellular matrix and their ability to activate specific receptors [77]. These issues will be resolved by determining the sequence of tissue-specific HS and by demonstrating whether specific HS sequences can modulate the binding specificity of FGFs beyond that determined by the specific FGFR and its alternative splice form in the presence of heparin.

A second area of research will aim to elucidate the developmental roles of all the FGFs, first alone and then in various combinations. This will include determining whether a single FGF with a defined developmental function interacts with one or multiple FGFRs. A third major frontier will be to elucidate the physiological roles of FGFs that are expressed in adult tissues. This will again involve testing combinations of FGFs in cases in which knockouts are viable and designing conditional alleles in cases of embryonic lethality. Major areas being considered include neuronal and cardiovascular physiology, neuronal regeneration and homeostasis and tissue repair.

The last major frontier will be to elucidate the primary roles of FGFs in genetic diseases and cancer. Several FGFs were initially cloned from human and animal tumors. Future work will be required to determine whether FGF activation is itself an etiological agent in primary human tumors or whether it is a progression factor in the pathogenesis of cancer. As functional roles for FGFs are elucidated in embryonic development, it is expected that various human birth defects and genetic diseases will be attributed to mutations in Fgf genes. These studies will probably lead to the development of pharmacogenetic agents to treat these diseases. Because a large number of skeletal diseases are caused by mutations in Fgfr genes, it is anticipated that mutations in some Fgf genes will also be involved in skeletal pathology.

Acknowledgements

This work was supported by NIH grants CA60673 and HD35692 and by a grant from the American Heart Association (to D.M.O.) and by the Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan and a grant from the Human Frontier Science Program, France (to N.I.).

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    This study identifies a novel FGF-related subfamily, termed fibroblast growth factor homologous factors (FHF). FHFs lack a classical signal sequence and contain nuclear localization signals. FHFs are expressed in the developing and adult nervous systems, suggesting a role in nervous system development and function.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  32. Yamamoto S, Mikami T, Ohbayashi N, Ohta M, Itoh N: Structure and expression of a novel isoform of mouse FGF homologous factor (FHF)-4.

    Biochim Biophys Acta 1998, 1398:38-41.

    Identification of alternative amino terminal coding exon for FHF4/FGF14.

    PubMed Abstract | Publisher Full Text OpenURL

  33. Munoz-Sanjuan I, Smallwood PM, Nathans J: Isoform diversity among fibroblast growth factor homologous factors is generated by alternative promoter usage and differential splicing.

    J Biol Chem 2000, 275:2589-2597.

    Characterization of multiple isoforms of Fhfs1-4/Fgfs 11-14, generated through the use of alternative 5' exons. Isoforms show different subcellular distributions and distinct expression patterns in developing and adult mouse tissues.

    PubMed Abstract | Publisher Full Text OpenURL

  34. Wang Q, McEwen DG, Ornitz DM: Subcellular and developmental expression of alternatively spliced forms of fibroblast growth factor 14.

    Mech Dev 2000, 90:283-287.

    Identification of isoforms of Fhf4/Fgf14 that result from the alternative usage of two different first exons. Isoforms show different subcellular localization and distinct expression patterns in developing and adult mouse tissues. Expression was observed in migrating and post migratory neurons.

    PubMed Abstract | Publisher Full Text OpenURL

  35. Antoine M, Reimers K, Dickson C, Kiefer P: Fibroblast growth factor 3, a protein with dual subcellular localization, is targeted to the nucleus and nucleolus by the concerted action of two nuclear localization signals and a nucleolar retention signal.

    J Biol Chem 1997, 272:29475-29481.

    Identification of an FGF3 CUG initiation site. This amino-terminal extended product is localized in both the nucleus/nucleolus and secretory pathway. The amino terminus contains both a signal sequence and a nuclear localization signal.

    PubMed Abstract | Publisher Full Text OpenURL

  36. Hogan BL: Morphogenesis.

    Cell 1999, 96:225-233.

    Review article highlighting the roles of multigene families, such as Fgfs, Bmps, Hedgehogs, Wnts and Egfs in morphogenesis.

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  37. Martin GR: The roles of FGFs in the early development of vertebrate limbs.

    Genes Dev 1998, 12:1571-1586.

    Review article summarizing data on the role of FGFs in vertebrate limb development. Demonstrates that FGFs play essential roles in signaling centers that control establishment, outgrowth and patterning of the limb bud.

    PubMed Abstract | Publisher Full Text OpenURL

  38. Lee PL, Johnson DE, Cousens LS, Fried VA, Williams LT: Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor.

    Science 1989, 245:57-60.

    This is the first cloning of an FGF receptor.

    PubMed Abstract OpenURL

  39. Johnson DE, Lee PL, Lu J, Williams LT: Diverse forms of a receptor for acidic and basic fibroblast growth factors.

    Mol Cell Biol 1990, 10:4728-4736.

    Identification of FGF receptor 1 variants which contain either two or three immunoglobulin-like domains. Identification of putative secreted forms of FGF receptor 1.

    PubMed Abstract OpenURL

  40. McKeehan WL, Wang F, Kan M: The heparan sulfate-fibroblast growth factor family: diversity of structure and function.

    Prog Nucleic Acid Res Mol Biol 1998, 59:135-176.

    This review presents models for FGF receptor activation by FGF and heparin. Also discussed are developmental roles for FGFs in liver and prostate development.

    PubMed Abstract OpenURL

  41. Miki T, Bottaro DP, Fleming TP, Smith CL, Burgess WH, Chan AM, Aaronson SA: Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene.

    Proc Natl Acad Sci USA 1992, 89:246-250.

    Demonstration that FGFR alternative splicing can regulate ligand binding specificity.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  42. Chellaiah AT, McEwen DG, Werner S, Xu J, Ornitz DM: Fibroblast growth factor receptor (FGFR) 3. Alternative splicing in immunoglobulin-like domain III creates a receptor highly specific for acidic FGF/FGF-1.

    J Biol Chem 1994, 269:11620-11627.

    Identification of an alternative splice form of FGFR3 with very restricted ligand binding properties.

    PubMed Abstract | Publisher Full Text OpenURL

  43. Naski MC, Ornitz DM: FGF signaling in skeletal development.

    Front Biosci 1998, 3:D781-D794.

    Review article highlighting the functions of the Fgfrs with a focus on roles in skeletal development.

    PubMed Abstract | Publisher Full Text OpenURL

  44. Yan G, Fukabori Y, McBride G, Nikolaropolous S, McKeehan WL: Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy.

    Mol Cell Biol 1993, 13:4513-4522.

    Demonstration that tumor progression can be accompanied by a change in Fgfr alternative splicing with consequent change in ligand binding specificity.

    PubMed Abstract OpenURL

  45. Orr-Urtreger A, Bedford MT, Burakova T, Arman E, Zimmer Y, Yayon A, Givol D, Lonai P: Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2).

    Dev Biol 1993, 158:475-486.

    Demonstration that alternative Fgfr splice forms are expressed preferentially in epithelial and mesenchymal lineages.

    PubMed Abstract | Publisher Full Text OpenURL

  46. Gilbert E, Del Gatto F, Champion-Arnaud P, Gesnel MC, Breathnach R: Control of BEK and K-SAM splice sites in alternative splicing of the fibroblast growth factor receptor 2 pre-mRNA.

    Mol Cell Biol 1993, 13:5461-5468.

    Identification of the mechanism regulating tissue-specific usage of alternative splice forms of Fgfr2.

    PubMed Abstract OpenURL

  47. Avivi A, Yayon A, Givol D: A novel form of FGF receptor-3 using an alternative exon in the immunoglobulin domain III.

    FEBS Lett 1993, 330:249-252.

    Identification of alternative splice forms of Fgfr3.

    PubMed Abstract | Publisher Full Text OpenURL

  48. Scotet E, Houssaint E: The choice between alternative IIIb and IIIc exons of the FGFR-3 gene is not strictly tissue-specific.

    Biochim Biophys Acta 1995, 1264:238-242.

    The less stringent alternative splicing choice between exons IIIb and IIIc of FGFR3 is in contrast with the very tissue-specific alternative splicing observed for FGFR2 in which epithelial cells use only the IIIb exon and fibroblasts use only the IIIc exon.

    PubMed Abstract | Publisher Full Text OpenURL

  49. Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M: Receptor specificity of the fibroblast growth factor family.

    J Biol Chem 1996, 271:15292-15297.

    The first comparison of the relative mitogenic activity of a large number of FGFs on cells expressing a single alternatively spliced FGFR 1-3 or FGFR4.

    PubMed Abstract | Publisher Full Text OpenURL

  50. Igarashi M, Finch PW, Aaronson SA: Characterization of recombinant human fibroblast growth factor (Fgf-10) reveals functional similarities with keratinocyte growth factor (Fgf-7).

    J Biol Chem 1998, 273:13230-13235.

    Demonstrates that the receptor-binding specificity of FGF10 is similar to that of the closely related FGF7.

    PubMed Abstract | Publisher Full Text OpenURL

  51. Miki T, Fleming TP, Bottaro DP, Rubin JS, Ron D, Aaronson SA: Expression cDNA cloning of the KGF receptor by creation of a transforming autocrine loop.

    Science 1991, 251:72-75.

    First cloning of a receptor for FGF7/KGF.

    PubMed Abstract OpenURL

  52. MacArthur CA, Lawshé A, Xu J, Santos-Ocampo S, Heikinheimo M, Chellaiah AT, Ornitz DM: FGF-8 isoforms activate receptor splice forms that are expressed in mesenchymal regions of mouse development.

    Development 1995, 121:3603-3613.

    Identification of alternatively spliced forms of FGF8 and demonstration that these molecules bind the mesenchymal splice forms of Fgfr2.

    PubMed Abstract | Publisher Full Text OpenURL

  53. Heikinheimo M, Lawshé A, Shackleford GM, Wilson DB, MacArthur CA: Fgf-8 expression in the post-gastrulation mouse suggests roles in the development of the face, limbs and central nervous system.

    Mech Dev 1994, 48:129-138.

    Identification of temporal and spatial patterns of Fgf8 expression in the developing mouse.

    PubMed Abstract | Publisher Full Text OpenURL

  54. Crossley PH, Martin GR: The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo.

    Development 1995, 121:439-451.

    Identification of alternative splice forms of Fgf8 and Fgf8 expression in the apical ectodermal ridge.

    PubMed Abstract | Publisher Full Text OpenURL

  55. Moscatelli D: High and low affinity binding sites for basic fibroblast growth factor on cultured cells: absence of a role for low affinity binding in the stimulation of plasminogen activator production by bovine capillary endothelial cells.

    J Cell Physiol 1987, 131:123-130.

    This paper challenges the role of cell surface heparan sulfate in FGFR activation but establishes a role for cell surface heparan sulfate in binding FGF.

    PubMed Abstract OpenURL

  56. Flaumenhaft R, Moscatelli D, Rifkin DB: Heparin and heparan sulfate increase the radius of diffusion and action of basic fibroblast growth factor.

    J Cell Biol 1990, 111:1651-1659.

    This paper demonstrates that the extracellular matrix can store FGF and limit its diffusion in tissues.

    PubMed Abstract OpenURL

  57. Mach H, Volkin DB, Burke CJ, Middaugh CR, Linhardt RJ, Fromm JR, Loganathan D, Mattsson L: Nature of the interaction of heparin with acidic fibroblast growth factor.

    Biochemistry 1993, 32:5480-5489.

    This paper establishes that FGF1 binds heparin at high density (one molecule every 4-5 saccharide units) and with high affinity (50-140 nM).

    PubMed Abstract OpenURL

  58. Herr AB, Ornitz DM, Sasisekharan R, Venkataraman G, Waksman G: Heparin-induced self-association of fibroblast growth factor-2. Evidence for two oligomerization processes.

    J Biol Chem 1997, 272:16382-16389.

    Presents analytical data that indicates that biologically active heparin octasaccharides can induce a monomer-dimer-tetramer assembly of FGF2.

    PubMed Abstract | Publisher Full Text OpenURL

  59. Moy FJ, Safran M, Seddon AP, Kitchen D, Bohlen P, Aviezer D, Yayon A, Powers R: Properly oriented heparin-decasaccharide-induced dimers are the biologically active form of basic fibroblast growth factor.

    Biochemistry 1997, 36:4782-4791.

    Evidence that a cis-oriented FGF2 dimer is the minimal biologically active structural unit of FGF2 in the presence of a decasaccharide.

    PubMed Abstract | Publisher Full Text OpenURL

  60. Ornitz DM, Yayon A, Flanagan JG, Svahn CM, Levi E, Leder P: Heparin is required for cell-free binding of basic fibroblast growth factor to a soluble receptor and for mitogenesis in whole cells.

    Mol Cell Biol 1992, 12:240-247.

    First study to show that heparin, FGF and an FGF receptor binding domain form a trimolecular complex in vitro. This paper also shows that this complex is essential for receptor activation on cells lacking heparan sulfate proteoglycan.

    PubMed Abstract OpenURL

  61. Rapraeger AC, Krufka A, Olwin BB: Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation.

    Science 1991, 252:1705-1708.

    The first study to demonstrate that cell surface heparan sulfate is directly involved in FGF cell signaling.

    PubMed Abstract OpenURL

  62. Yayon A, Klagsbrun M, Esko JD, Leder P, Ornitz DM: Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor.

    Cell 1991, 64:841-848.

    The first study to demonstrate that heparin is required for FGF to bind to an FGF receptor.

    PubMed Abstract | Publisher Full Text OpenURL

  63. Lin XH, Buff EM, Perrimon N, Michelson AM: Heparan sulfate proteoglycans are essential for FGF receptor signaling during Drosophila embryonic development.

    Development 1999, 126:3715-3723.

    The first genetic evidence that heparan sulfate glycosaminoglycans are essential for fibroblast growth factor receptor signaling in a well defined developmental context. These data support the model in which heparan sulfate facilitates FGF and/or FGF-FGFR oligomerization.

    PubMed Abstract | Publisher Full Text OpenURL

  64. Szebenyi G, Fallon JF: Fibroblast growth factors as multifunctional signaling factors.

    Int Rev Cytol 1999, 185:45-106.

    This is a comprehensive review that highlights all aspects of FGF biology including cell signaling, receptor binding and activation and roles for FGFs in embryonic development.

    PubMed Abstract OpenURL

  65. Schlessinger J, Plotnikov AN, Ibrahimi OA, Eliseenkova AV, Yeh BK, Yayon A, Linhardt RJ, Mohammadi M: Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization.

    Mol Cell 2000, 6:743-750.

    This paper presents a diffusion-based crystal structure which shows heparan fragments bound to both FGF and the FGFR in a head-to-head orientation.

    PubMed Abstract | Publisher Full Text OpenURL

  66. Chellaiah A, Yuan W, Chellaiah M, Ornitz DM: Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity.

    J Biol Chem 1999, 274:34785-34794.

    Identification of a second ligand-binding region on the FGF receptor.

    PubMed Abstract | Publisher Full Text OpenURL

  67. Meyers EN, Lewandoski M, Martin GR: An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination.

    Nat Genet 1998, 18:136-141.

    First null, hypomorphic and conditional allele created for an FGF. This study reveals requirements for Fgf8 during gastrulation, cardiac, craniofacial, forebrain, midbrain and cerebellar development.

    PubMed Abstract OpenURL

  68. Moon AM, Capecchi MR: Fgf8 is required for outgrowth and patterning of the limbs.

    Nat Genet 2000, 26:455-459.

    Demonstrates an essential role for Fgf8 in limb bud development.

    PubMed Abstract | Publisher Full Text OpenURL

  69. Lewandoski M, Sun X, Martin GR: Fgf8 signalling from the AER is essential for normal limb development.

    Nat Genet 2000, 26:460-463.

    Demonstrates an essential role for Fgf8 in limb bud development.

    PubMed Abstract | Publisher Full Text OpenURL

  70. Reifers F, Bohli H, Walsh EC, Crossley PH, Stainier DY, Brand M: Fgf8 is mutated in zebrafish acerebellar (ace) mutants and is required for maintenance of midbrain-hindbrain boundary development and somitogenesis.

    Development 1998, 125:2381-2395.

    Demonstrates a role for Fgf8 in midbrain hindbrain development in zebrafish by demonstrating genetic linkage between Fgf8 and the acerebellar (ace) mutation. Demonstrates that ace is probably a null mutation in Fgf8.

    PubMed Abstract | Publisher Full Text OpenURL

  71. Heisenberg CP, Brennan C, Wilson SW: Zebrafish aussicht mutant embryos exhibit widespread overexpression of ace (fgf8) and coincident defects in CNS development.

    Development 1999, 126:2129-2140.

    Identification of a genetic locus that may regulate Fgf8 (ace) expression in zebrafish.

    PubMed Abstract | Publisher Full Text OpenURL

  72. Hebert JM, Rosenquist T, Gotz J, Martin GR: FGF5 as a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations.

    Cell 1994, 78:1017-1025.

    Demonstrates that a null allele in the Fgf5 gene is allelic with the mouse angora mutation. Identifies an essential role for FGF5 in regulating the hair growth cycle.

    PubMed Abstract | Publisher Full Text OpenURL

  73. Carlton MBL, Colledge WH, Evans MJ: Crouzon-like craniofacial dysmorphology in the mouse is caused by an insertional mutation at the Fgf3/Fgf4 locus.

    Dev Dyn 1998, 212:242-249.

    Identification of a retroviral integration in the intragenic region between Fgf3 and Fgf4 in the Bulgy-eye (Bey) mutant mouse. Expression of both Fgf3 and Fgf4 is up-regulated in the cranial sutures of Bey mice. Phenocopies some features of Crouzon syndrome.

    PubMed Abstract | Publisher Full Text OpenURL

  74. White KE, Evans WE, O'Riordan JL, Speer MC, Econs MJ, Lorenz-Depiereux B, Grabowski M, Meitinger T, Strom TM: Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.

    Nat Genet 2000, 26:345-348.

    First identification of a missense mutation in an FGF ligand in a human genetic disease. Autosomal dominant hypophosphataemic rickets (ADHR) is characterized by low serum phosphorus concentrations, rickets, osteomalacia, lower extremity deformities, short stature, bone pain and dental abscesses.

    PubMed Abstract | Publisher Full Text OpenURL

  75. White KE, Jonsson KB, Carn G, Hampson G, Spector TD, Mannstadt M, Lorenz-Depiereux B, Miyauchi A, Yang IM, Ljunggren O, et al.: The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting.

    J Clin Endocrinol Metab 2001, 86:497-500.

    FGF-23, the gene mutated in ADHR, is a secreted protein and its mRNA is abundantly expressed by several different oncogenic hypophosphatemic osteomalacia tumors.

    PubMed Abstract | Publisher Full Text OpenURL

  76. Gecz J, Baker E, Donnelly A, Ming JE, McDonald-McGinn DM, Spinner NB, Zackai EH, Sutherland GR, Mulley JC: Fibroblast growth factor homologous factor 2 (FHF2): gene structure, expression and mapping to the Borjeson-Forssman-Lehmann syndrome region in Xq26 delineated by a duplication breakpoint in a BFLS-like patient.

    Hum Genet 1999, 104:56-63.

    Identification of linkage between FGF12/FHF2 and Borjeson-Forssman-Lehmann syndrome.

    PubMed Abstract | Publisher Full Text OpenURL

  77. Chang Z, Meyer K, Rapraeger AC, Friedl A: Differential ability of heparan sulfate proteoglycans to assemble the fibroblast growth factor receptor complex in situ.

    FASEB J 2000, 14:137-144.

    First paper to demonstrate that tissue-specific heparan sulfate molecules can affect patterns of FGF and FGF receptor binding in situ.

    PubMed Abstract | Publisher Full Text OpenURL

  78. Madiai F, Hackshaw KV, Chiu IM: Characterization of the entire transcription unit of the mouse fibroblast growth factor 1 (FGF-1) gene. Tissue-specific expression of the FGF-1.A mRNA.

    J Biol Chem 1999, 274:11937-11944.

    This paper defines the entire transcriptional unit of the mouse Fgf1 gene and shows that heart is the most abundant source of Fgf1.A mRNA.

    PubMed Abstract | Publisher Full Text OpenURL

  79. Abraham JA, Whang JL, Tumolo A, Mergia A, Friedman J, Gospodarowicz D, Fiddes JC: Human basic fibroblast growth factor: nucleotide sequence and genomic organization.

    EMBO J 1986, 5:2523-2528.

    First cloned member of the FGF family.

    PubMed Abstract OpenURL

  80. Brookes S, Smith R, Thurlow J, Dickson C, Peters G: The mouse homologue of hst/k-FGF: sequence, genome organization and location relative to int-2.

    Nucleic Acids Res 1989, 17:4037-4045.

    This paper idenitifies the mouse Fgf4 gene and shows that it is within 20 kb of the Fgf3 gene on chromosome 7.

    PubMed Abstract OpenURL

  81. Colvin JS, Feldman B, Nadeau JH, Goldfarb M, Ornitz DM: Genomic organization and embryonic expression of the mouse fibroblast growth factor 9 gene.

    Dev Dyn 1999, 216:72-88.

    Contains a detailed analysis of the embryonic expression patterns of Fgf9.

    PubMed Abstract | Publisher Full Text OpenURL

  82. Chiu IM, Liu Y, Payson RA: Isolation of yeast artificial chromosomes containing the entire transcriptional unit of the human FGF1 gene: a 720-kb contig spanning human chromosome 5q31.3->q32.

    Cancer Genet Cytogenet 1998, 106:1-10.

    Localization of the Fgf1 gene to the q31-q33 region of chromosome 5, a regions that includes a number of genes encoding growth factors, growth factor receptors, hormone/neurotransmitter receptors.

    PubMed Abstract | Publisher Full Text OpenURL

  83. Cox RD, Copeland NG, Jenkins NA, Lehrach H: Interspersed repetitive element polymerase chain reaction product mapping using a mouse interspecific backcross.

    Genomics 1991, 10:375-384.

    A rapid method to generate and map inter-repeat polymerase chain reaction products using DNA from interspecific backcross mice.

    PubMed Abstract OpenURL

  84. Lafage-Pochitaloff M, Galland F, Simonetti J, Prats H, Mattei MG, Birnbaum D: The human basic fibroblast growth factor gene is located on the long arm of chromosome 4 at bands q26-q27.

    Oncogene Res 1990, 5:241-244.

    Chromosomal localization of human FGF2.

    PubMed Abstract OpenURL

  85. Mattei MG, Pebusque MJ, Birnbaum D: Chromosomal localizations of mouse Fgf2 and Fgf5 genes.

    Mamm Genome 1992, 2:135-137.

    Mapping of Fgf2 and Fgf5 on mouse chromosome 4.

    PubMed Abstract OpenURL

  86. Kim HS, Crow TJ: Human proto-oncogene Int-2/FGF-3 map position 11q13.3-q13.4.

    Chromosome Res 1998, 6:579.

    Chromosomal localization of human FGF3.

    PubMed Abstract | Publisher Full Text OpenURL

  87. Yoshida CM, Wada M, Satoh H, Yoshida T, Sakamoto H, Miyagawa K, Yokota J, Koda T, Kakinuma M, Sugimura T, et al.: Human HST1 (HSTF1) gene maps to chromosome band 11q13 and coamplifies with the Int2 gene in human cancer.

    Proc Natl Acad Sci USA 1988, 85:4861-4864.

    Mapping of human FGF4 to chromosome 11q13. Both FGF3 and FGF4 were co-amplified in DNA from a stomach cancer and a vulvar carcinoma cell line.

    PubMed Abstract OpenURL

  88. Peters G, Kozak C, Dickson C: Mouse mammary tumor virus integration regions int-1 and int-2 map on different mouse chromosomes.

    Mol Cell Biol 1984, 4:375-378.

    Demonstration that MMTV can activate expression of FGF3 to initiate oncogenesis in mouse mammary epithelial cells.

    PubMed Abstract OpenURL

  89. Peters G, Brookes S, Smith R, Placzek M, Dickson C: The mouse homolog of the hst/k-FGF gene is adjacent to int-2 and is activated by proviral insertion in some virally induced mammary tumors.

    Proc Natl Acad Sci USA 1989, 86:5678-5682.

    Identification of a close linkage between Fgf3 and Fgf4 on mouse chromosome 7. Demonstration that either or both Fgf3 and Fgf4 can be activated by mouse mammary tumor virus integration.

    PubMed Abstract OpenURL

  90. Nguyen C, Roux D, Mattei MG, de Lapeyriere O, Goldfarb M, Birnbaum D, Jordan BR: The FGF-related oncogenes hst and int.2, and the bcl.1 locus are contained within one megabase in band q13 of chromosome 11, while the fgf.5 oncogene maps to 4q21.

    Oncogene 1988, 3:703-708.

    Identification of physical linkage between Fgf3 and Fgf4 on human chromosome 11.

    PubMed Abstract OpenURL

  91. deLapeyriere O, Rosnet O, Benharroch D, Raybaud F, Marchetto S, Planche J, Galland F, Mattei MG, Copeland NG, Jenkins NA, et al.: Structure, chromosome mapping and expression of the murine Fgf-6 gene.

    Oncogene 1990, 5:823-831.

    Localization of Fgf6 on mouse chromosome 6.

    PubMed Abstract OpenURL

  92. Marics I, Adelaide J, Raybaud F, Mattei MG, Coulier F, Planche J, de Lapeyriere O, Birnbaum D: Characterization of the HST-related FGF.6 gene, a new member of the fibroblast growth factor gene family.

    Oncogene 1989, 4:335-340.

    Cloning of FGF6 based on sequence similarity with FGF4. FGF6 was mapped to chromosome 12p13.

    PubMed Abstract OpenURL

  93. Zimonjic DB, Kelley MJ, Rubin JS, Aaronson SA, Popescu NC: Fluorescence in situ hybridization analysis of keratinocyte growth factor gene amplification and dispersion in evolution of great apes and humans.

    Proc Natl Acad Sci USA 1997, 94:11461-11465.

    Chromosomal localization of Fgf7 sequences in human and great ape genomes indicates that amplification and dispersion occurred in multiple discrete steps during evolution.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  94. Mattei MG, deLapeyriere O, Bresnick J, Dickson C, Birnbaum D, Mason I: Mouse Fgf7 (fibroblast growth factor 7) and Fgf8 (fibroblast growth factor 8) genes map to chromosomes 2 and 19 respectively.

    Mamm Genome 1995, 6:196-197.

    Mouse Fgf7 and Fgf8 genes were mapped to chromosomes 2F-G and 19C3-D, respectively.

    PubMed Abstract OpenURL

  95. Payson RA, Wu J, Liu Y, Chiu IM: The human Fgf-8 gene localizes on chromosome 10q24 and is subjected to induction by androgen in breast cancer cells.

    Oncogene 1996, 13:47-53.

    Mapping human FGF8 to chromosome 1Oq24.

    PubMed Abstract OpenURL

  96. Mattei MG, Penault-Llorca F, Coulier F, Birnbaum D: The human FGF9 gene maps to chromosomal region 13q11-q12.

    Genomics 1995, 29:811-812.

    Chromosomal localization of human FGF9 to 13q11-q12.

    PubMed Abstract | Publisher Full Text OpenURL

  97. Mattei MG, De Moerlooze L, Lovec H, Coulier F, Birnbaum D, Dickson C: Mouse fgf9 (fibroblast growth factor 9) is localized on chromosome 14.

    Mamm Genome 1997, 8:617-618. PubMed Abstract | Publisher Full Text OpenURL

  98. Emoto H, Tagashira S, Mattei MG, Yamasaki M, Hashimoto G, Katsumata T, Negoro T, Nakatsuka M, Birnbaum D, Coulier F, et al.: Structure and expression of human fibroblast growth factor-10.

    J Biol Chem 1997, 272:23191-23194.

    Cloning and mapping of human FGF10 to 5p12-p13. Demonstration that FGF10 is similar to FGF7 in both sequence and biological activity.

    PubMed Abstract | Publisher Full Text OpenURL

  99. Crackower MA, Heng HH, Tsui LC: Assignment of mouse fibroblast growth factor 10 (Fgf10) gene to the telomeric region of chromosome 13.

    Genomics 1998, 53:247-248.

    Mapping Fgf10 to mouse chromosome 13.

    PubMed Abstract | Publisher Full Text OpenURL

  100. Verdier AS, Mattei MG, Lovec H, Hartung H, Goldfarb M, Birnbaum D, Coulier F: Chromosomal mapping of two novel human FGF genes, FGF11 and FGF12.

    Genomics 1997, 40:151-154.

    Mapping human FGF11 and FGF12 to chromosome 17p12-p13 and 3q28, respectively.

    PubMed Abstract | Publisher Full Text OpenURL

  101. Hartung H, Lovec H, Verdier AS, Mattei MG, Coulier F, Goldfarb M, Birnbaum D: Assignment of Fgf12 to mouse chromosome bands 16B1->B3 by in situ hybridization.

    Cytogenet Cell Genet 1997, 76:185-186.

    Mapping mouse Fgf12 to chromosome 13B1-3.

    PubMed Abstract OpenURL

  102. Liu Y, Chiu IM: Assignment of Fgf12, the human Fgf homologous factor 1 gene, to chromosome 3q29->3qter by fluorescence in situ hybridization.

    Cytogenet Cell Genet 1997, 78:48-49.

    Mapping human FGF12 to chromosome 3q29-3qter.

    PubMed Abstract OpenURL

  103. Lovec H, Hartung H, Verdier AS, Mattei MG, Birnbaum D, Goldfarb M, Coulier F: Assignment of FGF13 to human chromosome band Xq21 by in situ hybridization.

    Cytogenet Cell Genet 1997, 76:183-184.

    Mapping FGF13 to human chromosome Xq21.

    PubMed Abstract OpenURL

  104. Xu J, Lawshe A, MacArthur CA, Ornitz DM: Genomic structure, mapping, activity and expression of fibroblast growth factor 17.

    Mech Dev 1999, 83:165-78.

    Expression patterns of Fgf17 and Fgf8 and demonstration that Fgf17 has similar receptor specificity, genomic organization and alternative splicing to Fgf8.

    PubMed Abstract | Publisher Full Text OpenURL

  105. Whitmore TE, Maurer MF, Sexson S, Raymond F, Conklin D, Deisher TA: Assignment of fibroblast growth factor 18 (FGF18) to human chromosome 5q34 by use of radiation hybrid mapping and fluorescence in situ hybridization.

    Cytogenet Cell Genet 2000, 90:231-233.

    Mapping FGF18 to human chromosome 5q34.

    PubMed Abstract | Publisher Full Text OpenURL

  106. Xie MH, Holcomb I, Deuel B, Dowd P, Huang A, Vagts A, Foster J, Liang J, Brush J, Gu Q, et al.: FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4.

    Cytokine 1999, 11:729-735.

    Identification of human Fgf19 and demonstration of in vitro biological activity.

    PubMed Abstract | Publisher Full Text OpenURL

  107. Kirikoshi H, Sagara N, Saitoh T, Tanaka K, Sekihara H, Shiokawa K, Katoh M: Molecular cloning and characterization of human FGF-20 on chromosome 8p21.3-p22.

    Biochem Biophys Res Commun 2000, 274:337-343.

    Cloning of human FGF20 and mapping to chromosome 8p21.3-p22. FGF20 is most closely related to FGF9 and FGF16. FGF20 mRNA was detected in a colon cancer cell line and at lower levels in human fetal tissues and primary tumors.

    PubMed Abstract | Publisher Full Text OpenURL

  108. Nishimura T, Nakatake Y, Konishi M, Itoh N: Identification of a novel FGF, FGF-21, preferentially expressed in the liver.

    Biochim Biophys Acta 2000, 1492:203-206.

    Cloning of Fgf21 an Fgf most closely related to Fgf19 and Fgf23.

    PubMed Abstract | Publisher Full Text OpenURL

  109. Nakatake Y, Hoshikawa M, Asaki T, Kassai Y, Itoh N: Identification of a novel fibroblast growth factor, FGF-22, preferentially expressed in the inner root sheath of the hair follicle.

    Biochim Biophys Acta 2001, 1517:460-463.

    Identification of Fgf22, a homolog of Fgf7 and Fgf10.

    PubMed Abstract | Publisher Full Text OpenURL

  110. Miller DL, Ortega S, Bashayan O, Basch R, Basilico C: Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice.

    Mol Cell Biol 2000, 20:2260-2268.

    The relatively mild phenotypic defects associated with loss of FGF2 led to the hypothesis that other FGFs partially compensate. However, FGF1-FGF2 double-knockout mice are viable and fertile and do not display any gross phenotypic defects.Thus Fgf1 null mice do not have a detectable phenotype and lack redundancy with Fgf2.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  111. Tobe T, Ortega S, Luna JD, Ozaki H, Okamoto N, Derevjanik NL, Vinores SA, Basilico C, Campochiaro PA: Targeted disruption of the FGF2 gene does not prevent choroidal neovascularization in a murine model.

    Am J Pathol 1998, 153:1641-1646.

    This study demonstrates that FGF2 is not required for the development of choroidal neovascularization.

    PubMed Abstract | Publisher Full Text OpenURL

  112. Ortega S, Ittmann M, Tsang SH, Ehrlich M, Basilico C: Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2.

    Proc Natl Acad Sci, USA 1998, 95:5672-5677.

    Mice lacking Fgf2 are viable, fertile and phenotypically indistinguishable from wild type. Although not essential for embryonic development, loss of FGF2 leads to defects in cortical neurogenesis and skin wound healing in mice.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  113. Zhou M, Sutliff RL, Paul RJ, Lorenz JN, Hoying JB, Haudenschild CC, Yin M, Coffin JD, Kong L, Kranias EG, et al.: Fibroblast growth factor 2 control of vascular tone.

    Nat Med 1998, 4:201-207.

    Mice lacking Fgf2 are morphologically normal but display decreased vascular smooth muscle contractility, low blood pressure and thrombocytosis.

    PubMed Abstract OpenURL

  114. Schultz JE, Witt SA, Nieman ML, Reiser PJ, Engle SJ, Zhou M, Pawlowski SA, Lorenz JN, Kimball TR, Doetschman T: Fibroblast growth factor-2 mediates pressure-induced hypertrophic response.

    J Clin Invest 1999, 104:709-719.

    Identification of a role for FGF2 in the pathogenesis of cardiac hypertrophy.

    PubMed Abstract | Publisher Full Text OpenURL

  115. Mansour SL: Targeted disruption of int-2 (fgf-3) causes developmental defects in the tail and inner ear.

    Mol Reprod Dev 1994, 39:62-67.

    The first member of the Fgf family to be knocked out in mice. Developmental defects were discovered in the inner ear and in outgrowth of the tail.

    PubMed Abstract OpenURL

  116. Feldman B, Poueymirou W, Papaioannou VE, DeChiara TM, Goldfarb M: Requirement of FGF-4 for postimplantation mouse development.

    Science 1995, 267:246-249.

    Fgf4 null embryos implant but die shortly thereafter. Fgf4 null embryos cultured in vitro displayed severely impaired proliferation of the inner cell mass.

    PubMed Abstract OpenURL

  117. Fiore F, Sebille A, Birnbaum D: Skeletal muscle regeneration is not impaired in Fgf6-/- mutant mice.

    Biochem Biophys Res Commun 2000, 272:138-143.

    Mice lacking Fgf6 have normal muscle regeneration. This is in contrast to the relatively severe phenotype noted by Floss et al. [118].

    PubMed Abstract | Publisher Full Text OpenURL

  118. Floss T, Arnold HH, Braun T: A role for Fgf-6 in skeletal muscle regeneration.

    Genes Dev 1997, 11:2040-2051.

    Mice lacking Fgf6 show a severe muscle regeneration defect with fibrosis and myotube degeneration.

    PubMed Abstract | Publisher Full Text OpenURL

  119. Fiore F, Planche J, Gibier P, Sebille A, Delapeyriere O, Birnbaum D: Apparent normal phenotype of Fgf6-/- mice.

    Int J Dev Biol 1997, 41:639-642.

    Mice lacking Fgf6 are phenotypically normal.

    PubMed Abstract OpenURL

  120. Guo L, Degenstein L, Fuchs E: Keratinocyte growth factor is required for hair development but not for wound healing.

    Genes Dev 1996, 10:165-175.

    Mice lacking Fgf7 have a unexpectedly subtle phenotype affecting hair growth.

    PubMed Abstract OpenURL

  121. Qiao J, Uzzo R, Obara-Ishihara T, Degenstein L, Fuchs E, Herzlinger D: FGF-7 modulates ureteric bud growth and nephron number in the developing kidney.

    Development 1999, 126:547-554.

    Identification of a second phenotype in mice lacking Fgf7. The developing ureteric bud and mature collecting system of Fgf7-null kidneys is markedly smaller than wild type and have 30% fewer nephrons than wild-type kidneys.

    PubMed Abstract | Publisher Full Text OpenURL

  122. Sun X, Meyers EN, Lewandoski M, Martin GR: Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo.

    Genes Dev 1999, 13:1834-1846.

    This study identifies Fgf8 as a gene essential for gastrulation and shows that signaling via FGF8 and/or FGF4 is required for cell migration away from the primitive streak.

    PubMed Abstract | Publisher Full Text OpenURL

  123. Shanmugalingam S, Houart C, Picker A, Reifers F, Macdonald R, Barth A, Griffin K, Brand M, Wilson SW: Ace/Fgf8 is required for forebrain commissure formation and patterning of the telencephalon.

    Development 2000, 127:2549-2561.

    Demonstration that Fgf8/Ace is required for the development of midline structures in the zebrafish forebrain.

    PubMed Abstract | Publisher Full Text OpenURL

  124. Colvin JS, Green RP, Schmahl J, Capel B, Ornitz DM: Male to female sex reversal in mice lacking fibroblast growth factor 9.

    Cell 2001, in press.

    This study demonstrates that FGF9 is essential for testicular mesenchymal growth, cord formation, and Sertoli and Leydig cell differentiation. FGF9 may also regulate mesonephric cell migration into the male gonad.

    OpenURL

  125. Ohuchi H, Hori Y, Yamasaki M, Harada H, Sekine K, Kato S, Itoh N: FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development.

    Biochem Biophys Res Commun 2000, 277:643-649.

    Diverse phenotypes of mice lacking Fgf10 closely resemble those of mice lacking FGFR2b. Major phenotypes include the absence of thyroid, pituitary, and salivary glands in addition to the previously described absence of limbs and lungs. Minor defects were observed in the formation of the teeth, kidneys, hair follicles, and digestive organs.

    PubMed Abstract | Publisher Full Text OpenURL

  126. Min H, Danilenko DM, Scully SA, Bolon B, Ring BD, Tarpley JE, DeRose M, Simonet WS: Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless.

    Genes Dev 1998, 12:3156-3161.

    Mice lacking Fgf10 exhibited perinatal lethality associated with complete absence of lungs. Fgf10 null mice also lack limbs. There is some disagreement with Sekine et al. [127] as to whether the apical ectodermal ridge transiently forms.

    PubMed Abstract | Publisher Full Text OpenURL

  127. Sekine K, Ohuchi H, Fujiwara M, Yamasaki M, Yoshizawa T, Sato T, Yagishita N, Matsui D, Koga Y, Itoh N, Kato S: Fgf10 is essential for limb and lung formation.

    Nat Genet 1999, 21:138-141.

    Mice lacking Fgf10 die at birth due to the lack of lung development beyond the trachea. Mice lacking Fgf10 also had complete truncation of the forelmbs and hindlimbs. In Fgf10 null embryos, limb bud formation was initiated but outgrowth of the limb buds did not occur.

    PubMed Abstract | Publisher Full Text OpenURL