Sites of Fgf signalling and perception during embryogenesis

成纤维细胞生长因子与其受体

October 2007Biol. Pharm. Bull.30(10) 1819—1825 (2007)1819

Review

The Fgf Families in Humans, Mice, and Zebra sh: Their Evolutional Processes and Roles in Development, Metabolism, and Disease

Nobuyuki ITOH

Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences;

Sakyo-ku, Kyoto 606–8501, Japan.

Received June 27, 2007

Fibroblast growth factors (Fgfs) were originally isolated as growth factors for broblasts. However, Fgfs arenow recognized as polypeptide growth factors of ca.150—250 amino acid residues with diverse biological activi-ties and expression pro les. The Fgf signaling system has been identi ed in multicelluar but not in unicellular or-ganisms. In contrast to the only two Fgfgenes and one Fgf receptor(Fgfr) gene in Caenorhabditis elegans, boththe human and mouse Fgfand Fgfrgene families comprise twenty-two and four members, respectively. Theirevolutional processes indicate that the Fgfand Fgfrgene families greatly co-expanded during the evolution ofearly vertebrates. The expansion of the Fgfand Fgfrgene families has enabled this signaling system to acquirediversity of function and a nearly ubiquitous involvement in many developmental and physiological processes.The zebra sh fgfgene family comprises twenty-seven members with several paralogs generated by an additionalgenome duplication. The mouse and zebra sh are useful models for studying gene functions. Fgfknockout micehave been generated. Several Fgfknockout mice die in the embryonic or early postnatal stages, indicating crucialroles for these genes in various developmental processes. However, other Fgfknockout mice survive with subtlephenotypic alterations. Their functions might be redundant. Studies using zebra sh embryos with mutated orknockdown fgfs also indicate that fgfs play crucial roles in development in that species. Although most Fgfs actin development in a paracrine and/or autocrine manner, some have potential roles in metabolism in an endocrinemanner. In humans, Fgf signaling disorders result in hereditary diseases and cancers.

Key words

broblast growth factor; broblast growth factor receptor; gene family; development; disease; metabolism

1.INTRODUCTION

In the development of multicellular organisms, varioussignaling pathways are activated in a highly coordinatedmanner to ensure proper morphogenesis. Secreted signalingmolecules such as broblast growth factors (Fgfs), bone mor-phogenic proteins (Bmps), Wnts, and Hedgehogs play crucialroles in development by in uencing the intracellular signal-ing events of their neighbors from a distance.1,2)Fgfs arepolypeptide growth factors with diverse biological activities.Most Fgfs mediate their biological responses by binding toand activating cell surface tyrosine kinase Fgf receptors(Fgfrs). The Fgf signalling system is required in multiple de-velopmental processes including differentiation, cell prolifer-ation, and migration.3—5)In this paper, I provide a succinctreview of the Fgfgene families in humans, mice, and ze-bra sh and their evolutionary processes and roles in develop-ment, metabolism, and disease.2.

THE HUMAN/MOUSE FGFGENE FAMILY

Two Fgfs, acidic Fgf (Fgf1) and basic Fgf (Fgf2), wereoriginally isolated from the brain and pituitary gland asgrowth factors for broblasts. The genes for Fgf1 and Fgf2are widely expressed in developing and adult tissues.6,7)Thereafter, seven Fgfs were also identi ed or isolated. Thegenes for Fgf3—Fgf6 were identi ed as oncogenes.8—11)Onthe other hand, Fgf7, Fgf8, and Fgf9 proteins were isolatedas growth factors for keratinocytes, an androgen-inducedgrowth factor from carcinoma cells, and a glia-activating fac-tor from glioma cells, respectively.12—14)These Fgfgenes areexpressed predominantly during embryonic development andare also expressed in restricted adult tissues, indicating their

potential roles in development.

Fgf1—Fgf9 have a conserved ca.120-amino acid residuecore with ca.30—70% sequence identity, although they areproteins of different sizes ranging from ca.150 to 250 aminoacid residues.3,4)We tried to identify new Fgfgenes by con-ducting homology-based polymerase chain reaction (PCR)and homology-based searches in nucleotide sequence data-bases based on their conserved amino acid sequences. Wesuccessfully isolated or identi ed Fgf10, Fgf16, Fgf17,Fgf18, Fgf20, and Fgf21by PCR15—20)and Fgf19, Fgf22,and Fgf23by searching nucleotide sequence databases.21—23)In addition, Smallwood et al.24)isolated or identi ed Fgf11—Fgf14genes from the retina by using a combination of ran-dom cDNA sequencing, homology-based searches of nu-cleotide sequence databases, and homology-based PCR.McWhirter et al.25)also isolated the Fgf15gene as a down-stream target of the chimeric homoeodomain oncoproteinE2A-Pbx1. Fgf1—Fgf23 have been identi ed in humans andmice. However, the human FGF15and mouse Fgf19geneshave not been identi ed. The location of the human FGF19and mouse Fgf15genes on chromosomes indicates thatFGF19is a human ortholog of mouse Fgf15. Thus thehuman and mouse Fgfgene families comprise twenty-twomembers.3,4)

Most Fgfs are secreted proteins with cleavable N-terminalsignal peptides.3)Fgf9, Fgf16, and Fgf20 with uncleaved bi-partite signal sequences are also secreted proteins.26,27)Bycontrast, Fgf1, Fgf2, and Fgf11—Fgf14 without N-terminalhydrophobic sequences are not typical secreted proteins.Fgf1 and Fgf2 might be released from damaged cells or byan exocytotic mechanism that is independent of the endo-plasmic reticulum-Golgi pathway.28)Fgf11—Fgf14 are notsecreted, but function within cells.29)

© 2007 Pharmaceutical Society of Japan

e-mail: itohnobu@pharm.kyoto-u.ac.jp

成纤维细胞生长因子与其受体

18203.THE HUMAN/MOUSE FGFRGENE FAMILY

Four Fgfrgenes, Fgfr1—Fgfr4, have been identi ed inhumans and mice.4)These genes encode receptor tyrosine ki-nases (ca.800 amino acids) that contain an extracellular lig-and-binding domain with three immunoglobulin domains (I,II, and III), a transmembrane domain, and a split intracellulartyrosine kinase domain. Fgfr1—Fgfr3encode two differentversions of immunoglobin-like domain III (IIIb and IIIc)generated by alternative mRNA splicing that utilizes one oftwo unique exons. The immunoglobulin-like domain III is anessential determinant of ligand-binding speci city. Thusseven Fgfr proteins (Fgfrs1b, 1c, 2b, 2c, 3b, 3c, and 4) withdiffering ligand-binding speci city are generated from fourFgfrgenes in vertebrates.30,31)

4.EVOLUTION OF THE FGFAND FGFRGENE FAMI-LIES

By phylogenetic analysis, the human FGFgene family canbe divided into seven subfamilies: FGF1, FGF4, FGF7,FGF8, FGF9, FGF11, and FGF19. The FGF1, FGF4,FGF7, FGF8, FGF9, FGF11, and FGF19subfamilies com-prise FGFs1and 2, FGFs4, 5, and 6, FGFs3, 7, 10, and 22,FGFs8, 17, and 18, FGFs9, 16, and 20, FGFs11, 4)

12, 13,and14, and FGFs19, 21, and 23, respectively (Fig. 1).Phylogenetic analysis indicates potential evolutionary rela-tionships in the gene family. However, it alone is not suf -cient to determine these relationships.32)Analysis of the loca-tion of genes on chromosomes also indicates potential evolu-tionary relationships in a gene family. In contrast to phylo-genetic analysis, gene location analysis indicates that thehuman FGFgene family can be divided into six subfamilies;FGF1/2/5, FGF3/4/6/19/21/23, FGF7/10/22, FGF8/17/18,FGF9/16/20, and FGF11/12/13/14(Fig. 2).4)Members of theFGF8, FGF9,and FGF11subfamilies from phylogeneticanalysis are consistent with those of the FGF7/10/22,FGF8/17/18, FGF9/16/20, and FGF11/12/13/14subfamiliesin the gene location analysis. However, gene location analy-sis indicates that the FGF4and FGF19subfamilies fromphylogenetic analysis should be combined into one subfam-ily, FGF3/4/6/19/21/23. FGF5is a member of the FGF4sub-family from phylogenetic analysis (Fig. 1). FGF5is closelylinked to the Annexin A3gene (ANXA3). FGF1and FGF2are also closely linked to ANXA6and ANXA5, respectively(Fig. 2). This indicates that FGF1, FGF2, and FGF5aremembers of the same subfamily, FGF1/2/5.

Fgfgenes have not been identi ed in unicellular organ-isms such as Escherichia coliand Saccharomyces cerevisiae.They have, however, been identi ed in multicelluar organ-isms from the nematode Caenorhabditis elegansto Homosapiens.4)Twenty-two FGFsand four FGFRshave beenidenti ed in humans. By contrast, only two Fgfgenes andone Fgfrgene have been identi ed in C. elegans. Analysis of the ascidian, Ciona intestinalis, genome has identi ed ve Fgfgenes and one Fgfrgene.33)Five Fgfgenes, Ci-Fgf3/7/10/22, Ci-Fgf4/5/6, Ci-Fgf8/17/18, Ci-Fgf9/16/20,and Ci-Fgf11/12/13/14, appear to be derived from genes an-cestral to the vertebrate Fgfsubfamilies (Fig. 3).

During evolution, the Fgfgene family appears to have ex-panded in two phases. In the rst phase, during early meta-V

ol. 30, No. 10

Fig.1.

Evolutionary Relationships within the Human FGFGene Family4)

Twenty-two FGFshave been identi ed. Phylogenetic analysis suggests that the FGFscan be arranged into seven subfamilies containing two to four members each. Branchlengths are proportional to the evolutionary distance between each gene. FGF19is ahuman ortholog of mouse Fgf15

.

Fig.2.Gene Locus Maps for FGFGenes on Human Chromosomes4)

Gene maps were constructed by examining human FGFgene loci using the EnsemblGenome Browser (/). FGFgene loci and closely linked genesare shown. Gene symbols are described according to the browser. The conservation ofgene order supports a model for large-scale genome duplication events.

zoan evolution, Fgfgenes increased from two or three to sixgenes by gene duplication. In the second phase, during theevolution of early vertebrates, the Fgfgene family expandedviatwo large-scale gen(om)e duplications. Three or fourmembers of the vertebrate subfamilies were potentially gen-erated in the second phase (Fig. 3).4)Four members of thevertebrate Fgfrgene family were also potentially generated

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