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Keywords:

  • ancestral FGF;
  • FGF receptor;
  • iFGF, hFGF, FGFR, gene family;
  • evolution;
  • phylogeny;
  • mouse;
  • vertebrate

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. IDENTIFICATION OF THE MOUSE FgF GENE FAMILY
  5. PHYOLOGENETIC AND GENE LOCATION ANALYSES OF THE MOUSE FgF GENE FAMILY
  6. EXON/INTRON ORGANIZATIONS OF MOUSE FgF GENES
  7. PHENOTYPES OF FgF KNOCKOUT MICE
  8. EVOLUTIONARY HISTORY OF THE MOUSE FgF GENE FAMILY
  9. PERSPECTIVES
  10. Acknowledgements
  11. REFERENCES

Fibroblast Growth Factors (FGFs) are polypeptides with diverse activities in development and physiology. The mammalian Fgf family can be divided into the intracellular Fgf11/12/13/14 subfamily (iFGFs), the hormone-like Fgf15/21/23 subfamily (hFGFs), and the canonical Fgf subfamilies, including Fgf1/2/5, Fgf3/4/6, Fgf7/10/22, Fgf8/17/18, and Fgf9/16/20. However, all Fgfs are evolutionarily related. We propose that an Fgf13-like gene is the ancestor of the iFgf subfamily and the most likely evolutionary ancestor of the entire Fgf family. Potential ancestors of the canonical and hFgf subfamilies, Fgf4-, Fgf5-, Fgf8-, Fgf9-, Fgf10-, and Fgf15-like, appear to have derived from an Fgf13-like ancestral gene. Canonical FGFs function in a paracrine manner, while hFGFs function in an endocrine manner. We conclude that the ancestral Fgfs for these subfamilies acquired this functional diversity before the evolution of vertebrates. During the evolution of early vertebrates, the Fgf subfamilies further expanded to contain three or four members in each subfamily. Developmental Dynamics 237:18–27, 2008. © 2007 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. IDENTIFICATION OF THE MOUSE FgF GENE FAMILY
  5. PHYOLOGENETIC AND GENE LOCATION ANALYSES OF THE MOUSE FgF GENE FAMILY
  6. EXON/INTRON ORGANIZATIONS OF MOUSE FgF GENES
  7. PHENOTYPES OF FgF KNOCKOUT MICE
  8. EVOLUTIONARY HISTORY OF THE MOUSE FgF GENE FAMILY
  9. PERSPECTIVES
  10. Acknowledgements
  11. REFERENCES

Fibroblast Growth Factors (FGFs) are polypeptides with diverse biological activities in multiple developmental and metabolic processes. The human/mouse Fgf gene family comprises 22 members. Most FGFs mediate their biological responses as extracellular proteins by binding to and activating cell surface tyrosine kinase FGF receptors (FGFRs) (Ornitz and Itoh,2001; Itoh and Ornitz,2004; Thisse and Thisse,2005). However, FGFs 11–14 function as intracellular proteins, hereafter referred to as iFGFs, and act in an FGF Receptor (FGFR)-independent manner (Goldfarb,2005).

The genes encoding FGFs have been identified in multicellular organisms ranging from Caenorhabditis elegans to humans (Itoh and Ornitz,2004). Two Fgf genes were found in C. elegans, whereas 22 Fgf genes have been identified in humans and mice, indicating that the Fgf gene family greatly expanded during the evolution of primitive metazoa to vertebrates. The Fgf family expanded in two phases (Itoh and Ornitz,2004; Popovici et al.,2005). In the first phase, during early metazoan evolution, Fgfs expanded from two or three to six genes by gene duplications. In the second phase, during the evolution of early vertebrates, the Fgf family expanded via two large-scale genome duplications. Phylogenetic and gene location analyses of the human Fgf family indicate that it comprises several subfamilies. Ancestors of the subfamilies were generated in the first phase. In the second phase, the subfamilies expanded to contain three or four members. However, their detailed expansion history remains mostly unclear.

According to the “exon theory of genes,” introns are expected to be ancient relics of primordial genes (Rogozin et al.,2005; de Roos,2007; Csuros et al.,2007), indicating that exon/intron organizations suggest the potential evolutionary history of a gene family. In addition, as ontogeny is expected to correlate with phylogeny (Seitz et al.,2006; Madsen,2007), functional roles of genes in development also provide useful clues for elucidating the evolutionary history of a gene family. As exon/intron organizations of vertebrate Fgf genes and their roles in development have been most studied in mice, we have examined the potential evolutionary history of the mouse Fgf gene family based on their gene organization and function in development along with phylogenetic and gene location analyses. In this review, we propose a model for the evolutionary history of the Fgf family, using the mouse Fgf family as a model.

IDENTIFICATION OF THE MOUSE FgF GENE FAMILY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. IDENTIFICATION OF THE MOUSE FgF GENE FAMILY
  5. PHYOLOGENETIC AND GENE LOCATION ANALYSES OF THE MOUSE FgF GENE FAMILY
  6. EXON/INTRON ORGANIZATIONS OF MOUSE FgF GENES
  7. PHENOTYPES OF FgF KNOCKOUT MICE
  8. EVOLUTIONARY HISTORY OF THE MOUSE FgF GENE FAMILY
  9. PERSPECTIVES
  10. Acknowledgements
  11. REFERENCES

Two FGFs, Acidic FGF (FGF1) and Basic FGF (FGF2), were originally isolated from the brain and pituitary gland as growth factors for fibroblasts (Gospodarowicz,1974; Gospodarowicz and Morgan,1974; Gospodarowicz et al.,1975). Thereafter, seven Fgfs, Fgf3–Fgf9, were also identified as oncogenes or isolated as growth factors for cultured cells (Dickson et al.,1991; Yoshida et al.,1991; Goldfarb et al.,1991; Coulier et al.,1991; Aaronson et al.,1991; Tanaka et al.,1992; Miyamoto et al.,1993). FGFs 1–9 range in size from ∼150 to 260 amino acid residues and have a conserved ∼120-amino acid residue core with ∼30 to 70% sequence identity (Ornitz and Itoh,2001; Itoh and Ornitz,2004). Based on their conserved amino acid sequences, Fgfs 10–14 and 16–23 were isolated by conducting a homology-based polymerase chain reaction or identified by homology-based searches in nucleotide sequence databases (Yamasaki et al.,1996; Smallwood et al.,1996; Miyake et al.,1998; Hoshikawa et al.,1998; Ohbayashi et al.,1998; Nishimura et al.,1999,2000; Ohmachi et al.,2000; Nakatake et al.,2001; Yamashita et al.,2000). In addition, Fgf15 was identified as a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx (McWhirter et al.,1997). Fgfs 1–23 have been identified in humans and mice. However, FGF19 is a human ortholog of mouse Fgf15. Thus, the mouse/human Fgf gene family comprises 22 members (Ornitz and Itoh,2001; Itoh and Ornitz,2004). FGFs 10–23 range in size from ∼160 to 250 amino acid residues and have a conserved ∼120-amino acid residue core (Ornitz and Itoh,2001; Itoh and Ornitz,2004).

Except for the iFGFs (FGF11–14) and hFGFs (FGF15/19, 21, 23), all other FGFs activate FGFRs with high affinity and different degrees of specificity (Ornitz et al.,1996; Zhang et al.,2006). We refer to these FGFs as canonical FGFs. Canonical FGFs are secreted (extracellular proteins) that bind to FGFRs and induce their dimerization and the phosphorylation of specific cytoplasmic tyrosine residues (Eswarakumar et al.,2005). Four Fgfr genes, Fgfr1–Fgfr4, have been identified in humans and mice. These genes encode receptor tyrosine kinases (∼800 amino acids) that contain an extracellular ligand-binding domain with three immunoglobulin domains (I, II, and III), a transmembrane domain, and a split intracellular tyrosine kinase domain. Fgfr1–Fgfr3 encode two different versions of immunoglobin-like domain III (IIIb and IIIc) generated by alternative mRNA splicing that utilizes one of two unique exons. The immunoglobulin-like domain III is an essential determinant of ligand-binding specificity (Johnson and Williams,1993). Thus, seven FGFR proteins (FGFRs 1b, 1c, 2b, 2c, 3b, 3c, and 4) differing in ligand-binding specificity are generated from four Fgfr genes in vertebrates (Ornitz et al.,1996; Zhang et al.,2006). In contrast, although iFGFs bear strong sequence similarity to canonical FGFs, their biochemical and functional properties are largely unrelated to those of canonical FGFs. Current data suggest that iFGFs act in an FGFR-independent manner. They have been shown to interact with intracellular domains of voltage-gate sodium channels and with the neuronal mitogen-activated protein kinase scaffold protein, islet-brain-2 (reviewed in Goldfarb,2005).

Canonical FGFs and the hFGF subfamily can be further characterized based on the mechanism by which they are released from cells. FGFs 3–8, 10, 15, 17, 18, 21, 22, and 23 are secreted proteins with cleavable amino terminal signal peptides (Ornitz and Itoh,2001). FGFs 9, 16, and 20 are also secreted proteins, but contain uncleavable bipartite signal sequences (Miyakawa et al,1999; Revest et al.,2000). By contrast, FGFs 1 and 2 do not have identifiable signal sequences but nevertheless can be found in extracellular locations. FGFs 1 and 2 might be released from damaged cells or by an exocytotic mechanism that is independent of the endoplasmic reticulum-Golgi pathway (Mignatti et al.,1992). It has also been reported that exogenously added FGF2 can be translocated to the nucleus where it can interact with and activate nuclear targets (Bonnet et al.,1996; Bailly et al.,2000). However, the physiological significance of FGF2 action in the nucleus remains unclear.

The canonical FGFs all have binding sites for acidic glycosaminoglycans including heparin and heparan sulfate (Ornitz,2000). In the presence of heparan sulfate, FGFs stably bind to FGFRs, which lead to the formation of 2:2:2 FGF-FGFR-heparan sulfate dimers (Mohammadi et al.,2005). In addition, acidic glycosaminoglycans in the form of heparan sulfate proteoglycans function to retain these FGFs in the vicinity of FGF-producing sites, such that they primarily act in a paracrine manner. By contrast, the hFGFs have low-affinity heparin-binding sites and have been found to act in an endocrine manner (Tomlinson et al.,2002; Lundasen et al.,2006; Kharitonenkov et al.,2005,2007; Fukumoto and Yamashita,2007; Liu and Quarles,2007).

PHYOLOGENETIC AND GENE LOCATION ANALYSES OF THE MOUSE FgF GENE FAMILY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. IDENTIFICATION OF THE MOUSE FgF GENE FAMILY
  5. PHYOLOGENETIC AND GENE LOCATION ANALYSES OF THE MOUSE FgF GENE FAMILY
  6. EXON/INTRON ORGANIZATIONS OF MOUSE FgF GENES
  7. PHENOTYPES OF FgF KNOCKOUT MICE
  8. EVOLUTIONARY HISTORY OF THE MOUSE FgF GENE FAMILY
  9. PERSPECTIVES
  10. Acknowledgements
  11. REFERENCES

Phylogenetic analysis of the mouse Fgf gene family identifies seven subfamilies: Fgf1 (1,2), Fgf4 (4,5,6), Fgf7 (7,10,22), Fgf8 (8,17,18), Fgf9 (9,16,20), iFgfs (11,12,13,14), and hFgfs (15, 21, 23) (Fig. 1) that are essentially consistent with those of the human FGF family (Itoh and Ornitz,2004). However, phylogenetic analysis alone is not sufficient to determine all evolutionary relationships (Horton et al.,2003). Analysis of gene loci on chromosomes also indicates potential evolutionary relationships within a gene family. We have examined mouse Fgf gene loci and conserved chromosomal gene location (synteny). In contrast to the phylogenetic analysis, the conserved gene location analysis indicates that the mouse Fgf gene family may more meaningfully be divided into six subfamilies: Fgf1/2/5, Fgf3/4/6/15/21/23, Fgf7/10/22, Fgf8/17/18, Fgf9/16/20, and iFgfs (Fgf11/12/13/14) (Fig. 2). The mouse Fgf subfamilies derived from the gene location analysis are also essentially consistent with the human Fgf subfamilies (Itoh and Ornitz,2004). Members of the Fgf7, Fgf8, Fgf9, and iFgf subfamilies from the gene location analysis are consistent with those of the Fgf7/10/22, Fgf8/17/18, Fgf9/16/20, and iFgf subfamilies from the phylogenetic analysis. Fgf5, a member of the Fgf4 subfamily in the phylogenetic analysis (Fig. 1), is however more closely linked to Fgf2 by gene location analysis. Both Fgf5 and Fgf2 are closely linked to Annexin A3 (Anxa3) and Annexin 5 (Anxa5), respectively (Fig. 2). This indicates that Fgf1, Fgf2, and Fgf5 are members of a common subfamily, FGF1/2/5.

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Figure 1. Evolutionary relationships within the mouse Fgf gene family and C. intestinalis Fgf11/12/13/14. Twenty-two Fgfs have been identified in mice. The apparent evolutionary relationships of the mouse Fgf family and C. intestinalis Fgf11/12/13/14 were examined by CLUSTRALW (http://align.genome.jp/). Phylogenetic analysis suggests that the Fgfs can be divided into seven subfamilies containing two to four members each. Branch lengths are proportional to the evolutionary distance between each gene.

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Figure 2. Chromosomal gene loci maps for mouse Fgfs. Gene loci maps were constructed by examining mouse Fgf gene loci using the Ensembl Genome Browser (http://www.ensembl.org/). Fgf gene loci and closely linked genes are shown. The bar lengths are not proportional to the distances between genes. Gene symbols are described according to the browser. The conservation of gene orders in the Fgf subfamiles supports a model for large-scale genome duplication events.

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Conserved gene location is observed among Fgf4, Fgf6, Fgf15, Fgf21, and Fgf23, indicating that these Fgfs belong to the same subfamily (Fig. 2). In addition, although Fgf3 is a member of the Fgf7 subfamily according to the phylogenetic and functional analysis, the gene location analysis indicates that Fgf3 is linked to Fgf4 and Fgf6, indicating that these are members of the same subfamily. However, the phylogenetic analysis and consideration of the biochemical and functional properties described above indicate that the hFgfs (Fgf15, Fgf21, and Fgf23) are distinct from Fgf3, Fgf4, and Fgf6. Therefore, these Fgfs should be divided into the Fgf3/4/6 and hFgf subfamilies. In summary, we propose that the secreted Fgfs should be divided into six subfamilies with three members in each; the canonical Fgfs (Fgf1/2/5, Fgf3/4/6, Fgf7/10/22, Fgf8/17/18, Fgf9/16/20) and the hFgfs (Fgf/15/21/23) (Fig. 2).

EXON/INTRON ORGANIZATIONS OF MOUSE FgF GENES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. IDENTIFICATION OF THE MOUSE FgF GENE FAMILY
  5. PHYOLOGENETIC AND GENE LOCATION ANALYSES OF THE MOUSE FgF GENE FAMILY
  6. EXON/INTRON ORGANIZATIONS OF MOUSE FgF GENES
  7. PHENOTYPES OF FgF KNOCKOUT MICE
  8. EVOLUTIONARY HISTORY OF THE MOUSE FgF GENE FAMILY
  9. PERSPECTIVES
  10. Acknowledgements
  11. REFERENCES

It is proposed that introns are relics of primordial genes (Rogozin et al.,2005; de Roos,2007; Csuros et al.,2007). This leads to the hypothesis that exon/intron organization can be used to infer the evolutionary history of a gene family. To this end, we have examined the exon/intron organizations of mouse Fgf genes. The conserved FGF core domain in the coding region of Fgf4 is divided by two introns (Fig. 3). The intron locations are highly conserved in the core regions of all canonical Fgfs and the hFgfs (data not shown). These two introns are also conserved in the core regions of the iFgf subfamily, indicating that iFgfs, hFgfs, and canonical Fgfs are evolutionarily related to each other (data not shown). However, two additional introns are also located outside of the core region of Fgf13 within sequences encoding the amino and carboxy terminal domains of the protein (Fig. 3). The positions of these four introns are also highly conserved among the other iFGFs (data not shown).

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Figure 3. Schematic representations of Fgf4 and Fgf13 intron locations. Fgf4 and Fgf13 are shown as representatives of the canonical Fgf subfamilies and iFgf subfamily, respectively. Arrowheads indicate the positions of introns. The positions of two introns in Fgf4 and four introns in Fgf13 are conserved among canonical Fgfs and iFgfs. SP and Core indicate a secreted signal sequence and core region, respectively. The numbers refer to the positions of amino acid residues. The introns are 0.4–5.8 Kbp long.

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Several Fgfs have acquired alternatively spliced amino terminal ends. Alternative spliced variants of Fgf8 and Fgf17 are generated from distinct splice sites that divide the “first” exon into four (in humans) sub-exons (MacArthur et al.,1995; Gemel et al.,1996; Xu et al.,1999; Olsen et al.,2006). Similarly, the iFgfs have acquired alternatively spliced amino terminal variants that are generated by alternative utilization of distinct first exons (reviewed in Goldfarb,2005). Importantly, none of these alternative splicing events affects the sequences of the conserved FGF core domain.

PHENOTYPES OF FgF KNOCKOUT MICE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. IDENTIFICATION OF THE MOUSE FgF GENE FAMILY
  5. PHYOLOGENETIC AND GENE LOCATION ANALYSES OF THE MOUSE FgF GENE FAMILY
  6. EXON/INTRON ORGANIZATIONS OF MOUSE FgF GENES
  7. PHENOTYPES OF FgF KNOCKOUT MICE
  8. EVOLUTIONARY HISTORY OF THE MOUSE FgF GENE FAMILY
  9. PERSPECTIVES
  10. Acknowledgements
  11. REFERENCES

Biological function of mouse Fgfs in development and physiology also provide useful clues to the evolutionary history of the Fgf gene family. Most Fgf genes have been disrupted by homologous recombination in mice. Phenotypes range from early embryonic lethality to subtle changes in adult physiology (Table 1 and Fig. 4). Fgf4 and Fgf8 knockout mice die at early embryonic stages. Fgf4 and Fgf8 have essential roles in blastocyst formation and gastrulation, respectively (Feldman et al.,1995; Sun et al.,1999). Fgf9, Fgf10, and Fgf18 knockout mice died shortly after birth. Fgf10 is critical for epithelial–mesenchymal interactions necessary for the development of epithelial components of multiple organs (Min et al.,1998; Sekine et al.,1999; Ohuchi et al.,2000; Sakaue et al.,2002). Fgf9 and Fgf18 have essential roles in the development of mesenchymal components of multiple organs (Colvin et al.,2001a,2001b, Ohbayashi et al.,2002; Liu et al.,2002; Usui et al.,2004). In contrast, Fgf15 knockout mice die at variable times during embryonic and postnatal stages of development. FGF15 functions in the development of the cardiac outflow tract (Vincentz et al.,2005) but also acts as an endocrine hormone in postnatal life (Inagaki et al.,2005). Other Fgf knockout mice either are viable or die during postnatal stages (Table 1). Conditional knockouts of Fgfs that have essential roles early in development have also revealed important functions for these Fgfs at later times of development (Moon et al.,2000; Moon and Capecchi2000; Sun et al.,2000; Chi et al.,2003; Lewandoski et al.,2000).

Table 1. Phenotypes in Fgf Knockout Mice
GenePhenotype 
  1. Phenotypes of most Fgf knockout mice have been published (reviewed in Ornitz and Itoh,2001; Itoh and Ornitz,2004). Fgf16 and Fgf21 knockout mice are viable (N. Itoh et al., unpublished data). Fgf22 knockout mice are also viable (H. Umemori, personal communication). Phenotypes of Fgf11, Fgf13, and Fgf20 knockout mice remain unclear. E, embryonic day; PD, postnatal day; PW, postnatal week. Asterisks indicate potential prototypes of the Fgf subfamilies. —, indicates unknown phenotypes.

iFgf subfamily  
 Fgf11
 Fgf12ViableNeuromuscular function
 Fgf13*
 Fgf14ViableNeurological function
Fgf3/4/6 subfamily  
 Fgf3ViableInner ear, tail and CNS development
 Fgf4*Lethal, E4–5Blastocyte formation
 Fgf6ViableSubtle, muscle regeneration
Fgf1/2/5 subfamily  
 Fgf1ViableNone identified
 Fgf2ViableCardiovascular, skeletal, and neuronal development
 Fgf5*ViableHair development
Fgf8/17/18 subfamily  
 Fgf8*Lethal, E8Gastrulation development
 Fgf17ViableCerebellar development
 Fgf18Lethal, PD0Skeletal and lung development
Fgf9/16/20 subfamily  
 Fgf9*Lethal, PD0Lung, heart, vascular, GI tract, and testis development
 Fgf16ViableHeart development
 Fgf20
Fgf7/10/22 subfamily  
 Fgf7ViableSubtle, muscle regeneration
 Fgf10*Lethal, PD0Multiple organ development
 Fgf22Viable
hFgf subfamily  
 Fgf15*Lethal, E13.5-PD21Heart development and bile acid metabolism
 Fgf21Viable
 Fgf23Lethal, PW4-13Phosphate and vitamin D metabolism
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Figure 4. Earliest identified roles for ancestral Fgfs in mouse embryonic development. Fgf4 and Fgf8 have essential roles in blastocyte formation and gastrulation, respectively. Fgf10 is essential for the development of multiple organs and tissues including the limbs, lungs, and white adipose tissue. Fgf9 is essential for the development of the lungs, heart, cecum, and testes. Fgf15 functions in cardiac outflow tract development. E, embryonic day. Arrowheads indicate the stage of earliest identified phenotypes of null mutants.

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EVOLUTIONARY HISTORY OF THE MOUSE FgF GENE FAMILY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. IDENTIFICATION OF THE MOUSE FgF GENE FAMILY
  5. PHYOLOGENETIC AND GENE LOCATION ANALYSES OF THE MOUSE FgF GENE FAMILY
  6. EXON/INTRON ORGANIZATIONS OF MOUSE FgF GENES
  7. PHENOTYPES OF FgF KNOCKOUT MICE
  8. EVOLUTIONARY HISTORY OF THE MOUSE FgF GENE FAMILY
  9. PERSPECTIVES
  10. Acknowledgements
  11. REFERENCES

The coding regions of the iFgfs are divided by four introns, while the coding regions of canonical Fgfs and hFgfs are divided by two introns. Consistent with the idea that introns are relics of primordial genes (Rogozin et al.,2005; de Roos,2007), these organizations indicate that the iFgf subfamily is the likely ancestor of the canonical Fgf families.

Numerous examples exist in which phylogenetic relationships appear to correspond with gene function at very early developmental stages (Seitz et al.,2006; Madsen,2007). This model suggests that FGF family members with very early functions in development may represent the prototype genes for their subfamily. By examining early developmental phenotypes of Fgf knockout mice as a guide, one can therefore make predictions of prototype members of Fgf subfamilies. The iFgf subfamily comprises Fgf11–Fgf14. Fgf12 and Fgf14 knockout mice are viable and have neurological phenotypes (Wang et al.,2002; Xiao et al.,2007; Goldfarb et al.,2007; Laezza et al.,2007). Although Fgf11 and Fgf13 knockout mice have not been reported, the expression of these genes in the central and peripheral nervous system suggests that these genes will also be found to function in neurodevelopment or neurophysiology. Experiments with Xenopus embryos indicate that Fgf13 is essential for neural differentiation in early embryonic development (Nishimoto and Nishida,2007). In addition, the C. intestinalis Fgf11/12/13/14, an ancestor of the vertebrate iFgf subfamily (Satou et al.,2002), is most homologous (57% amino acid identity in the core region) to Fgf13, although phylogenetic analysis between the mouse iFgf subfamily and the C. intestinalis Fgf11/12/13/14 has not clearly indicated their relationship (Fig. 1). Thus, Fgf13 appears most similar to an ancestral member of the iFgf subfamily.

All canonical Fgf subfamilies and the hFgfs comprise three members. Phenotypes of knockout mice for all Fgf3/4/6, Fgf7/10/22, Fgf8/17/18, and hFgf subfamily members have been reported. Knockout studies indicate that Fgf4, Fgf10, Fgf8, and Fgf15 have the most severe phenotypes at early developmental stages within their corresponding families and can thus be considered as the ancestral members of their subfamilies (Fig. 4). Of the members of the Fgf9/16/20 subfamily, Fgf9 is essential during embryonic stages, whereas Fgf16 knockout mice are viable (N. Itoh et al., unpublished data). Although phenotypes of Fgf20 knockout mice have not been reported, we tentatively have assigned an Fgf9-like gene as the ancestor of the Fgf9/16/20 subfamily. Knockout mice for the Fgf1/2/5 subfamily are all viable with relatively subtle phenotypes (Miller et al.,2000; Hebert et al.,1994). FGF1 and FGF2 lack signal peptides while FGF5 functions as a typical secreted protein. As the ancestral members of other canonical Fgf subfamilies are typical secreted proteins, we assign an Fgf5-like gene as the ancestor of the Fgf1/2/5 subfamily.

No conserved gene order was observed among ancestors of the Fgf subfamilies, indicating that the ancestors were generated by gene duplications, not by genome duplications. The ancestral gene of the Fgf family, which is tentatively assigned to Fgf13-like, encodes an intracellular protein without a secretory signal sequence, whereas the ancestral members of the other Fgf subfamilies encode secreted proteins with identifiable secretory signal sequences. In addition, although Fgf13 has four introns within its coding regions, all other ancestral Fgfs have only two introns. These results indicate that the ancestral members of the canonical Fgf subfamilies and hFgfs were derived from an Fgf13-like ancestral gene accompanied by loss of two introns. Of the canonical Fgfs, Fgf4 is required at the earliest stages of development, indicating that an Fgf4-like gene may be the ancestor of the canonical Fgf subfamilies (Fig. 4). From these results, we propose a model for the evolutionary history of the Fgf family (Figs. 5 and 6) with an Fgf13-like gene as the ancestral Fgf. An Fgf4-like gene was then generated from Fgf13-like by a gene duplication event followed by gene translocation. During this evolution, Fgf4-like lost two introns in the first and third exons of its coding region and acquired a cleavable amino terminal signal sequence in the first exon. Fgf5, Fgf8, Fgf9, and Fgf10 were then generated from Fgf4 by gene duplications followed by gene translocations. Cleavable secreted signal sequences and the intron positions were conserved in Fgf4, Fgf5, Fgf8, and Fgf10 expansions. The Fgf9/16/20 subfamily appears to have formed next with the evolution of an uncleaved bipartite signal sequence in an Fgf9-like ancestral gene.

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Figure 5. Evolutionary history of the mouse Fgf gene family. The Fgf family comprises 22 members. Fgf13-like is an ancestral gene of the Fgf family. Fgf4-like is an ancestral gene of the canonical Fgf family. Fgf4-like was generated from Fgf13-like by a gene duplication. Fgf5-like, Fgf8-like, Fgf9-like, Fgf10-like, and Fgf15-like were generated from Fgf4-like by gene duplications. These expansions occurred before the evolution of vertebrates. Each Fgf subfamily expanded to contain three or four members via two large-scale genome duplications during the evolution of early vertebrates.

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Figure 6. Functional evolutionary history of ancestors of the mouse Fgf gene family. Fgf13-like encoding an intracellular molecule is the ancestral gene of the Fgf family. Fgf4-like was generated from Fgf13-like by a gene duplication. During this evolution, Fgf4-like acquired a cleavable secreted signal sequence. Fgf5-like, Fgf8-like, Fgf9-like, and Fgf10-like were generated from Fgf4-like by gene duplications. Cleavable secreted signal sequences were conserved in Fgf-like5, Fgf8-like, and Fgf10-like. A cleavable secreted signal sequence also evolved into an uncleaved bipartite signal sequence in Fgf9-like. These Fgfs with heparin-binding sites function as proliferation or differentiation factors in a paracrine manner. Fgf15-like, generated from Fgf4-like by a cis-gene duplication, lost its high-affinity heparin-binding capacity and acquired affinity for an alternative co-factor (βKotho). These changes facilitated acquisition of a new function as an endocrine metabolic regulatory molecule.

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All canonical FGFs have high-affinity heparin-binding sites and act in a paracrine manner. However, the hFGFs have low-affinity heparin-binding sites. We thus propose that an Fgf15-like gene was derived from Fgf4-like by a cis-gene duplication accompanied by loss of its high-affinity heparin-binding capacity, thus allowing it to function as an endocrine molecule. The hFGF family also acquired affinity for alternative co-factors, Klotho and βKlotho, required for signaling in target tissues (see below).

As most ancestors of the Fgf subfamilies have been identified in the ascidian, C. intestinalis, Fgf family expansion must have occurred before the evolution of vertebrates (Itoh and Ornitz,2004). Ancestors of the canonical Fgf subfamilies have distinct receptor-binding specificity (Zhang et al.,2006). However, the Fgfr family expanded during the evolution of early vertebrates (Itoh and Ornitz,2004), indicating that canonical FGFs acquired diversity in receptor specificity during the evolution of early vertebrates.

Conserved gene orders are observed among members of each Fgf subfamily, indicating that each subfamily expanded into three or four members via two large-scale genome duplications during the evolution of early vertebrates (Itoh and Ornitz,2004). Although each canonical FGF has distinct receptor binding specificity, each member of an FGF subfamily has similar receptor specificity (Zhang et al.,2006). The most notable example of this is the ability of FGF9, FGF16, and FGF20 to bind FGFR3b in addition to c splice forms of FGFRs 1–3. In contrast, other canonical FGF subfamilies bind either b or c splice forms of FGFRs but not both.

PERSPECTIVES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. IDENTIFICATION OF THE MOUSE FgF GENE FAMILY
  5. PHYOLOGENETIC AND GENE LOCATION ANALYSES OF THE MOUSE FgF GENE FAMILY
  6. EXON/INTRON ORGANIZATIONS OF MOUSE FgF GENES
  7. PHENOTYPES OF FgF KNOCKOUT MICE
  8. EVOLUTIONARY HISTORY OF THE MOUSE FgF GENE FAMILY
  9. PERSPECTIVES
  10. Acknowledgements
  11. REFERENCES

The human/mouse Fgf gene family comprises 22 members with high-sequence similarity (Itoh and Ornitz,2004). However, their roles and mechanisms of action are highly diverse. FGF11–FGF14 (iFGFs) function as intracellular proteins in an FGFR-independent manner (Wang et al,2000; Goldfarb,2005). In contrast, canonical FGFs function as extracellular proteins in an FGFR-dependent manner.

Canonical FGFs mediate their biological responses by binding to and activating FGFRs. Seven FGFR proteins (Fgfrs1b, 1c, 2b, 2c, 3b, 3c, and 4) with differing ligand-binding specificity are generated from four Fgfr genes in vertebrates (Ornitz et al.,1996; Zhang et al.,2006). Canonical FGFs have heparin-binding sites that bind to extracellular acidic glycosaminoglycans. Acidic glycosaminoglycans function as FGF cofactors to facilitate efficient activation of FGFRs (Ornitz,2000). In addition, acidic glycosaminoglycans limit the diffusion of FGFs, localizing their activity to the vicinity of FGF-producing cells (Flaumenhaft et al.,1990). In contrast, hFGFs have poor heparin-binding affinity and act on target cells far from their site of production in an endocrine manner (Tomlinson et al.,2002; Lundasen et al.,2006; Kharitonenkov et al.,2005,2007; Fukumoto et al.,2007; Liu et al.,2007). In addition, FGF15, FGF21, and FGF23 require co-receptors, Klotho or βKlotho, to activate FGFRs (Ogawa et al.,2007; Urakawa et al.,2006). These co-receptors are specifically expressed in target cells and are required for the specific actions of these FGFs in target tissues. These findings indicate that hFGFs have evolved as novel metabolic regulators along with corresponding novel mechanisms of regulation.

Loss-of-function studies in mice have identified many other functions of FGFs. Most members of the Fgf family have been targeted in mice. Phenotypes range from early embryonic lethality to subtle changes in the physiology of adult mice, to no identifiable phenotype (Fgf1). Most canonical FGFs have essential roles as proliferation or differentiation factors in the development of various organs and tissues. In contrast, hFGFs have important roles as hormones that regulate bile acid metabolism, phosphate and vitamin D metabolism, and energy metabolism at postnatal stages (Shimada et al.,2004; Inagaki et al.,2005; Inagaki et al.,2007; Badman et al.,2007). Several of the Fgfs that exhibit early embryonic lethality as null mutations have also been studied later in development by conditional gene targeting and have been found to have many additional activities. Additionally, redundancy between FGFs, both within subfamilies and across subfamilies, has been identified. For example, redundancy between Fgf4 and Fgf8 in limb bud development was revealed by conditional, limb bud–specific, targeting of Fgf4 and Fgf8 (Moon et al.,2000; Moon and Capecchi,2000; Sun et al.,2000,2002; Lewandoski et al.,2000; Boulet et al.,2004). Redundancy between Fgf3 and Fgf8 occurs in otic vesicle and hindbrain development (Maroon et al.,2002; Walshe et al.,2002).

The studies of human diseases also have identified many potential functions of FGFs. Human hereditary disorders in FGF signaling result in diverse diseases consistent with the wide range of action of FGFs. Autosomal dominant hypophosphataemic rickets are caused by mutations in FGF23 that stabilize the FGF23 protein (ADHR Consortium,2000; White et al.,2001). FGF23 also functions as a humoral phosphaturic factor responsible for tumor-induced osteomalacia (Shimada et al.,2001). Both aplasia of lacrimal and salivary glands and lacrimo-auriculo-dento-digital syndrome are caused by mutations in FGF10 (Entesarian et al.,2005,2007; Milunsky et al.,2006; Rohmann et al.,2006). Michel aplasia is caused by mutations in FGF3 (Tekin et al.,2007). FGF20 is a potential risk factor for Parkinson's disease (van der Walt et al.,2004; Satake et al.,2007). FGF13 is a candidate gene for Börjeson-Forssman-Lehmann syndrome (Gecz et al.,1999) and a hereditary spinocerebellar ataxia syndrome (SCA27) is caused by mutations in FGF14 (van Swieten et al.,2003; Dalski et al,2005).

Since all human FGF gene loci have been identified, it is likely that mapping studies will uncover other genetic diseases that involve additional members of the FGF family. Additionally, an abundance of mutations in Fgfrs result in a variety of skeletal dysplasia syndromes (reviewed in Ornitz and Marie,2002), suggesting that mutations in Fgfs will also be found to affect skeletal development or homeostasis.

As described above, FGF signaling is critical for many developmental and metabolic processes in vertebrates, and disorders in Fgf signaling result in various human diseases. The proposed functional evolutionary history of the Fgf family will be useful to elucidate additional functions, redundancies, and networks in development and metabolism.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. IDENTIFICATION OF THE MOUSE FgF GENE FAMILY
  5. PHYOLOGENETIC AND GENE LOCATION ANALYSES OF THE MOUSE FgF GENE FAMILY
  6. EXON/INTRON ORGANIZATIONS OF MOUSE FgF GENES
  7. PHENOTYPES OF FgF KNOCKOUT MICE
  8. EVOLUTIONARY HISTORY OF THE MOUSE FgF GENE FAMILY
  9. PERSPECTIVES
  10. Acknowledgements
  11. REFERENCES

This work was supported in part by grants 18659021 and 19390021 from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to N.I.), the Takeda Science Foundation, Japan (to N.I.), the Mitsubishi Foundation, Japan (to N.I.), the National Institutes of Health grants HL07666401 and HD049808 (to D.M.O.), and the March of Dimes Foundation (to D.M.O.).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. IDENTIFICATION OF THE MOUSE FgF GENE FAMILY
  5. PHYOLOGENETIC AND GENE LOCATION ANALYSES OF THE MOUSE FgF GENE FAMILY
  6. EXON/INTRON ORGANIZATIONS OF MOUSE FgF GENES
  7. PHENOTYPES OF FgF KNOCKOUT MICE
  8. EVOLUTIONARY HISTORY OF THE MOUSE FgF GENE FAMILY
  9. PERSPECTIVES
  10. Acknowledgements
  11. REFERENCES
  • Aaronson SA, Bottaro DP, Miki T, Ron D, Finch PW, Fleming TP, Ahn J, Taylor WG, Rubin JS. 1991. Keratinocyte growth factor. A fibroblast growth factor family member with unusual target cell specificity. Ann NY Acad Sci 63: 6277.
  • ADHR Consortium 2000. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26: 345348.
  • Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. 2007. Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARalpha and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States. Cell Metab 5: 426437.
  • Bailly K, Soulet F, Leroy D, Amalric F, Bouche G. 2000. Uncoupling of cell proliferation and differentiation activities of basic fibroblast growth factor. FASEB J 14: 333344.
  • Bonnet H, Filhol O, Truchet I, Brethenou P, Cochet C, Amalric F, Bouche G. 1996. Fibroblast growth factor-2 binds to the regulatory beta subunit of CK2 and directly stimulates CK2 activity toward nucleolin. J Biol Chem 271: 2478124787.
  • Boulet AM, Moon AM, Arenkiel BR, Capecchi MR. 2004. The roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth. Dev Biol 273: 361372.
  • Chi CL, Martinez S, Wurst W, Martin GR. 2003. The isthmic organizer signal FGF8 is required for cell survival in the prospective midbrain and cerebellum. Development 130: 26332644.
  • Colvin JS, Green RP, Schmahl J, Capel B, Ornitz DM. 2001a. Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell 104: 875889.
  • Colvin JS, White AC, Pratt SJ, Ornitz DM. 2001b. Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme. Development 128: 20952106.
  • Coulier F, Ollendorff V, Marics I, Rosnet O, Batoz M, Planche J, Marchetto S, Pebusque M-J, deLapeyriere O, Birnbaum D. 1991. The FGF6 gene within the FGF multigene family. Ann NY Acad Sci 638: 5361.
  • Csuros M, Holey JA, Rogozin IB. 2007. In search of lost introns. Bioinformatics 23: i87i96.
  • Dalski A, Atici J, Kreuz FR, Hellenbroich Y, Schwinger E, Zuhlke C. 2005. Mutation analysis in the fibroblast growth factor 14 gene: frameshift mutation and polymorphisms in patients with inherited ataxias. Eur J Hum Genet 13: 118120.
  • de Roos AD. 2007. Conserved intron positions in ancient protein modules. Biol Direct 2: 7.
  • Dickson C, Fuller-Pace F, Kiefer P, Acland P, MacAllan D, Peters G. 1991. Expression, processing, and properties of int-2. Ann NY Acad Sci 638: 1826.
  • Entesarian M, Matsson H, Klar J, Bergendal B, Olson L, Arakaki R, Hayashi Y, Ohuchi H, Falahat B, Bolstad AI, Jonsson R, Wahren-Herlenius M, Dahl N. 2005. Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands. Nat Genet 37: 125127.
  • Entesarian M, Dahlqvist J, Shashi V, Stanley CS, Falahat B, Reardon W, Dahl N. 2007. FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG). Eur J Hum Genet 15: 379382.
  • Eswarakumar VP, Lax I, Schlessinger J. 2005. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16: 139149.
  • Feldman B, Poueymirou W, Papaioannou VE, DeChiara TM, Goldfarb M. 1995. Requirement of FGF-4 for postimplantation mouse development. Science 267: 246249.
  • Flaumenhaft R, Moscatelli D, Rifkin DB. 1990. Heparin and heparan sulfate increase the radius of diffusion and action of basic fibroblast growth factor. J Cell Biol 111: 16511659.
  • Fukumoto S, Yamashita T. 2007. FGF23 is a hormone-regulating phosphate metabolism: unique biological characteristics of FGF23. Bone 40: 1190-1195.
  • Gecz J, Baker E, Donnelly A, Ming JE, McDonald-McGinn DM, Spinner NB, Zackai EH, Sutherland GR, Mulley JC. 1999. 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 104: 5663.
  • Gemel J, Gorry M, Ehrlich GD, MacArthur CA. 1996. Structure and sequence of human FGF8. Genomics 35: 253257.
  • Goldfarb M. 2005. Fibroblast growth factor homologous factors: evolution, structure, and function. Cytokine Growth Factor Rev 16: 21520.
  • Goldfarb M, Bates B, Drucker B, Hardin J, Haub O. 1991. Expression and possible functions of the FGF-5 gene. Ann NY Acad Sci 638: 3852.
  • Goldfarb M, Schoorlemmer J, Williams A, Diwakar S, Wang Q, Huang X, Giza J, Tchetchik D, Kelley K, Vega A, Matthews G, Rossi P, Ornitz DM, D'Angelo E. 2007. Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage-gated sodium channels. Neuron 55: 449463.
  • Gospodarowicz D. 1974. Localization of a fibroblast growth factor and its effect alone and with hydrocortisone on 3T3 cell growth. Nature 249: 123127.
  • Gospodarowicz D, Moran J. 1974. Effect of a fibroblast growth factor, insulin, dexamethasone, and serum on the morphology of BALB/c 3T3 cells. Proc Natl Acad Sci USA 71: 46484652.
  • Gospodarowicz D, Weseman J, Moran J. 1975. Presence in brain of a mitogenic agent promoting proliferation of myoblasts in low density culture. Nature 256: 216219.
  • Hebert JM, Rosenquist T, Gotz J, Martin GR. 1994. FGF5 as a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations. Cell 78: 10171025.
  • Horton AC, Mahadevan NR, Ruvinsky I, Gibson-Brown JJ. 2003. Phylogenetic analyses alone are insufficient to determine whether genome duplication(s) occurred during early vertebrate evolution. J Exp Zool B Mol Dev Evol 299: 4153.
  • Hoshikawa M, Ohbayashi N, Yonamine A, Konishi M, Ozaki K, Fukui S, Itoh N. 1998. Structure and expression of a novel fibroblast growth factor, FGF-17, preferentially expressed in the embryonic brain. Biochem Biophys Res Commun 244: 187191.
  • Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, Gerard RD, Repa JJ, Mangelsdorf DJ, Kliewer SA. 2005. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2: 217225.
  • Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA. 2007. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab 5: 415425.
  • Itoh N, Ornitz DM. 2004. Evolution of the Fgf and Fgfr gene families. Trends Genet 20: 563569.
  • Johnson DE, Williams LT. 1993. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res 60: 141.
  • Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB. 2005. FGF-21 as a novel metabolic regulator. J Clin Invest 115: 16271635.
  • Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT, Hansen BC, Shanafelt AB, Etgen GJ. 2007. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148: 7747781.
  • Laezza F, Gerber BR, Lou, J, Kozel MA, Hartman H, Craig AM, Ornitz DM, Nerbonne JM. 2007. The Fgf14(F145S) mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability. J Neurosci 27: 1203312044.
  • Lewandoski M, Sun X, Martin GR. 2000. Fgf8 signalling from the AER is essential for normal limb development. Nat Genet 26: 460463.
  • Liu S, Quarles LD. 2007. How fibroblast growth factor 23 works. J Am Soc Nephrol 18: 16371647.
  • Liu Z, Xu J, Colvin JS, Ornitz DM. 2002. Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev 16: 859869.
  • Lundasen T, Galman C, Angelin B. 2006. Rudling M., Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J Intern Med 260: 530536.
  • MacArthur CA, Lawshe A, Xu J, Santos-Ocampo S, Heikinheimo M, Chellaiah AT, Ornitz DM. 1995. FGF-8 isoforms activate receptor splice forms that are expressed in mesenchymal regions of mouse development. Development 121: 36033613.
  • Madsen OD. 2007. Pancreas phylogeny and ontogeny in relation to a “pancreatic stem cell.” C R Biol 330: 534537.
  • Maroon H, Walshe J, Mahmood R, Kiefer P, Dickson C, Mason I. 2002. Fgf3 and Fgf8 are required together for formation of the otic placode and vesicle. Development 129: 20992108.
  • McWhirter JR, Goulding M, Weiner JA, Chun J, Murre C. 1997. A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1. Development 124: 32213232.
  • Mignatti P, Morimoto T, Rifkin DB. 1992. Basic fibroblast growth factor, a protein devoid of secretory signal sequence, is released by cells via a pathway independent of the endoplasmic reticulum-Golgi complex. J Cell Physiol 151: 8193.
  • Miller DL, Ortega S, Bashayan O, Basch R, Basilico C. 2000. Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice. Mol Cell Biol 20: 22602268.
  • Milunsky JM, Zhao G, Maher TA, Colby R, Everman DB. 2006. LADD syndrome is caused by FGF10 mutations. Clin Genet 69: 349354.
  • Min H, Danilenko DM, Scully SA, Bolon B, Ring BD, Tarpley JE, DeRose M, Simonet WS. 1998. Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev 12: 31563161.
  • Miyakawa K, Hatsuzawa K, Kurokawa T, Asada M, Kuroiwa T, Imamura T. 1999. A hydrophobic region locating at the center of fibroblast growth factor-9 is crucial for its secretion. J Biol Chem 274: 2935229357.
  • Miyake A, Konishi M, Martin FH, Hernday NA, Ozaki K, Yamamoto S, Mikami T, Arakawa T, Itoh N. 1998. Structure and expression of a novel member, FGF-16, on the fibroblast growth factor family. Biochem Biophys Res Commun. 243: 148152.
  • Miyamoto M, Naruo K, Seko C, Matsumoto S, Kondo T, Kurokawa T. 1993. Molecular cloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property. Mol Cell Biol 13: 4251v4259.
  • Mohammadi M, Olsen SK, Goetz R. 2005. A protein canyon in the FGF-FGF receptor dimer selects from an a la carte menu of heparan sulfate motifs. Curr Opin Struct Biol 15: 506516.
  • Moon AM, Capecchi MR. 2000. Fgf8 is required for outgrowth and patterning of the limbs. Nat Genet 26: 455459.
  • Moon AM, Boulet AM, Capecchi MR. 2000. Normal limb development in conditional mutants of Fgf4. Development 127: 989996.
  • Nakatake Y, Hoshikawa M, Asaki T, Kassai Y, Itoh N. 2001. Identification of a novel fibroblast growth factor, FGF-22, preferentially expressed in the inner root sheath of the hair follicle. Biochim Biophys Acta 1517: 460463.
  • Nishimoto S, Nishida E. 2007. Fibroblast growth factor 13 is essential for neural differentiation in Xenopus early embryonic development. J Biol Chem 283: 2425524261.
  • Nishimura T, Utsunomiya Y, Hoshikawa M, Ohuchi H, Itoh N. 1999. Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain. Biochim Biophys Acta 1444: 148151.
  • Nishimura T, Nakatake Y, Konishi M, Itoh N. 2000. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta 1492: 203206.
  • Ogawa Y, Kurosu H, Yamamoto M, Nandi A, Rosenblatt KP, Goetz R, Eliseenkova AV, Mohammadi M, Kuro-o M. 2007. BetaKlotho is required for metabolic activity of fibroblast growth factor 21. Proc Natl Acad Sci USA 104: 74327437.
  • Ohbayashi N, Hoshikawa M, Kimura S, Yamasaki M, Fukui S, Itoh N. 1998. Structure and expression of the mRNA encoding a novel fibroblast growth factor, FGF-18. J Biol Chem 273: 1816118164.
  • Ohbayashi N, Shibayama M, Kurotaki Y, Imanishi M, Fujimori T, Itoh N, Takada S. 2002. FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev 16: 870879.
  • Ohmachi S, Watanabe Y, Mikami T, Kusu N, Ibi T, Akaike A, Itoh N. 2000. FGF-20, a novel neurotrophic factor, preferentially expressed in the substantia nigra pars compacta of rat brain. Biochem Biophys Res Commun 277: 355360.
  • Ohuchi H, Hori Y, Yamasaki M, Harada H, Sekine K, Kato S, Itoh N. 2000. FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development. Biochem Biophys Res Commun 277: 643649.
  • Olsen SK, Li JY, Bromleigh C, Eliseenkova AV, Ibrahimi OA, Lao Z, Zhang F, Linhardt RJ, Joyner AL, Mohammadi M. 2006. Structural basis by which alternative splicing modulates the organizer activity of FGF8 in the brain. Genes Dev 20: 185198.
  • Ornitz DM. 2000. FGFs, heparan sulfate and FGFRs: complex interactions essential for development. Bioessays 22: 108112.
  • Ornitz DM, Itoh N. 2001. Fibroblast growth factors. Genome Biol 2: 3005.13005.12.
  • Ornitz DM, Marie PJ. 2002. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev 16: 14461465.
  • Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M. 1996. Receptor specificity of the fibroblast growth factor family. J Biol Chem 271: 1529215297.
  • Popovici C, Roubin R, Coulier F, Birnbaum D. 2005. An evolutionary history of the FGF superfamily. Bioessays 27: 849857.
  • Revest JM, DeMoerlooze L, Dickson C. 2000. Fibroblast growth factor 9 secretion is mediated by a non-cleaved amino-terminal signal sequence. J Biol Chem 275: 80838090.
  • Rogozin IB, Sverdlov AV, Babenko VN, Koonin EV. 2005. Analysis of evolution of exon-intron structure of eukaryotic genes. Brief Bioinform 6: 118134.
  • Rohmann E, Brunner HG, Kayserili H, Uyguner O, Nurnberg G, Lew ED, Dobbie A, Eswarakumar VP, Uzumcu A, Ulubil-Emeroglu M, Leroy JG, Li Y, Becker C, Lehnerdt K, Cremers CW, Yuksel-Apak M, Nurnberg P, Kubisch C, Schlessinger J, van Bokhoven H, Wollnik B. 2006. Mutations in different components of FGF signaling in LADD syndrome. Nat Genet 38: 414417.
  • Sakaue H, Konishi M, Ogawa W, Asaki T, Mori T, Yamasaki M, Takata M, Ueno H, Kato S, Kasuga M, Itoh N. 2002. Requirement of fibroblast growth factor 10 in development of white adipose tissue. Genes Dev 16: 908912.
  • Satake W, Mizuta I, Suzuki S, Nakabayashi Y, Ito C, Watanabe M, Takeda A, Hasegawa K, Sakoda S, Yamamoto M, Hattori N, Murata M, Toda T. 2007. Fibroblast growth factor 20 gene and Parkinson's disease in the Japanese population. Neuroreport 18: 937940.
  • Satou Y, Imai KS, Satoh N. 2002. Fgf genes in the basal chordate Ciona intestinalis. Dev Genes Evol 212: 432438.
  • Seitz V, Hummel M, Stein H, Papadopoulos N, Zemlin M, Joehrens K, Anagnostopoulos I. 2006. Evidence of haematopoiesis within the developing human diencephalon. Correlations with vertebrate phylogeny. Pathobiology 73: 5562.
  • Sekine K, Ohuchi H, Fujiwara M, Yamasaki M, Yoshizawa T, Sato T, Yagishita N, Matsui D, Koga Y, Itoh N, Kato S. 1999. Fgf10 is essential for limb and lung formation. Nat Genet 21: 138141.
  • Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T. 2001. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 98: 65006505.
  • Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T. 2004. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113: 561568.
  • Smallwood PM, Munoz-Sanjuan I, Tong P, Macke JP, Hendry SHC, Gilbert DJ, Copeland NG, Jenkins NA, Nathans J. 1996. Fibroblast growth factor (FGF) homologous factors: new members of the FGF family implicated in nervous system development. Proc Natl Acad Sci USA 93: 98509857.
  • Sun X, Meyers EN, Lewandoski M, Martin G.R. 1999. Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev 13: 18341846.
  • Sun X, Lewandoski M, Meyers EN, Liu YH, Maxson RE Jr, Martin GR. 2000. Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development. Nat Genet 25: 8386.
  • Sun X, Mariani FV, Martin GR. 2002. Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature 418: 501508.
  • Tanaka A, Miyamoto K, Minamino N, Takeda M, Sato B, Matsuo H, Matsumoto K. 1992. Cloning and characterization of an androgen-induced growth factor essential for the androgen-dependent growth of mouse mammary carcinoma cells. Proc Natl Acad Sci USA 89: 89288932.
  • Tekin M, Hismi BO, Fitoz S, Ozdag H, Cengiz FB, Sirmaci A, Aslan I, Inceoglu B, Yuksel-Konuk EB, Yilmaz ST, Yasun O, Akar N. 2007. Homozygous mutations in fibroblast growth factor 3 are associated with a new form of syndromic deafness characterized by inner ear agenesis, microtia, and microdontia. Am J Hum Genet 80: 338344.
  • Thisse B, Thisse C. 2005. Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev Biol 287: 390402.
  • Tomlinson E, Fu L, John L, Hultgren B, Huang X, Renz M, Stephan JP, Tsai SP, Powell-Braxton L, French D, Stewart TA. 2002. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 143: 17411747.
  • Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T. 2006. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444: 770774.
  • Usui H, Shibayama M, Ohbayashi N, Konishi M, Takada S, Itoh N. 2004. Fgf18 is required for embryonic lung alveolar development. Biochem Biophys Res Commun 322: 887892.
  • van der Walt JM, Noureddine MA, Kittappa R, Hauser MA, Scott WK, McKay R, Zhang F, Stajich JM, Fujiwara K, Scott BL, Pericak-Vance MA, Vance JM, Martin ER. 2004. Fibroblast growth factor 20 polymorphisms and haplotypes strongly influence risk of Parkinson disease. Am J Hum Genet 74: 11211127.
  • van Swieten JC, Brusse E, de Graaf BM, Krieger E, van de Graaf R, de Koning I, Maat-Kievit A, Leegwater P, Dooijes D, Oostra BA, Heutink P. 2003. A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia. Am J Hum Genet 72: 191199.
  • Vincentz JW, McWhirter JR, Murre C, Baldini A, Furuta Y. 2005. Fgf15 is required for proper morphogenesis of the mouse cardiac outflow tract. Genesis 41: 192201.
  • Walshe J, Maroon H, McGonnell IM, Dickson C, Mason I. 2002. Establishment of hindbrain segmental identity requires signaling by FGF3 and FGF8. Curr Biol 12: 11171123.
  • Wang Q, McEwen DG, Ornitz DM. 2000. Subcellular and developmental expression of alternatively spliced forms of fibroblast growth factor 14. Mech Dev 90: 283287.
  • Wang Q, Bardgett ME, Wong M, Wozniak DF, Lou J, McNeil BD, Chen C, Nardi A, Reid DC, Yamada K, Ornitz DM. 2002. Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14. Neuron 35: 2538.
  • White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ. 2001. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int 60: 20792086.
  • Xiao M, Xu L, Laezza F, Yamada K, Feng S, Ornitz DM. 2007. Impaired hippocampal synaptic transmission and plasticity in mice lacking fibroblast growth factor 14. Mol Cell Neurosci 34: 366377.
  • Xu J, Lawshe A, MacArthur CA, Ornitz DM. 1999. Genomic structure, mapping, activity and expression of fibroblast growth factor 17. Mech Dev 83: 165178.
  • Yamasaki M, Miyake A, Tagashira S, Itoh N. 1996. Structure and expression of the rat mRNA encoding a novel member of the fibroblast growth factor family. J Biol Chem 271: 1591815921.
  • Yamashita T, Yoshioka M, Itoh N. 2000. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun 277: 494498.
  • Yoshida T, Sakamoto H, Miyagawa K, Sugimura T, Terada M. 1991. Characterization of the hst-1 gene and its product. Ann NY Acad Sci 638: 2737.
  • Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. 2006. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 281: 1569415700.