Sites of Fgf signalling and perception during embryogenesis(2)

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