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Zebrafish VEGF receptors: a guideline to nomenclature.

Bussmann J, Lawson N, Zon L, Schulte-Merker S, Zebrafish Nomenclature Committ - PLoS Genet. (2008)

View Article: PubMed Central - PubMed

Affiliation: Hubrecht Laboratory (NIOB-KNAW NIOB), Utrecht, The Netherlands.

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In placental mammals (eutherians), there exist three paralogous genes of the vascular endothelial growth factor (VEGF) receptor family, namely FLT1 (also named VEGFR1), KDR (also named FLK1 and VEGFR2), and FLT4 (also named VEGFR3)... In the zebrafish, four genes encoding VEGF receptor proteins have been identified: the FLT1 orthologue ,, the FLT4 orthologue, and two genes with highest similarity to KDR/Flk1... However, the recent identification of a second potential KDR/FLK1 orthologue ,,, which in fact is more similar to the human gene, has caused confusion over the evolutionary relationships of zebrafish and mammalian VEGF receptors... It was therefore hypothesized that zebrafish contains duplicated KDR genes, which were consequently called kdra (the gene originally called flk1) and kdrb (the gene that is most similar to human KDR)... Second, synteny analysis showed that the loci containing the zebrafish flk1/kdra and kdrb have been conserved throughout vertebrate evolution (Figure 1B), strongly indicating the presence of both genes in the common ancestor of fish and mammals and the loss of a fourth VEGF receptor in the eutherian lineage (after the divergence of marsupial and placental mammals)... Although representing separate classes, experimental data revealed significant functional similarity of zebrafish flk1/kdra and kdrb... Furthermore, zebrafish VEGF can bind and activate both flk1/kdra and kdrb... Finally, flk1/kdra and kdrb genetically interact: knockdown of kdrb in a flk1/kdra mutant background resulted in similar phenotypes as those observed in embryos in which vegf was knocked down or in which a downstream signaling component, phospholipase-cγ1, is mutated ( and N... Lawson, unpublished data)... Therefore, to reflect that flk1/kdra is a prominent receptor in VEGF-A signaling in zebrafish, while at the same time indicating that it represents a fourth class of vertebrate VEGF receptors (and is not the result of a teleost gene duplication), we propose to rename this gene kdr-like... As the zebrafish kdrb gene is clearly orthologous to mammalian KDR, we propose to rename this gene kdr.

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Adapted from Bussmann et al., 2007 [4].A. Unrooted neighbor-joining tree of vertebrate VEGF receptors. Different colors represent different classes of VEGF receptors. Purple shading was used to highlight the fourth vertebrate VEGF receptor class, which is missing in eutherian mammals. The node representing this fourth class was supported in 1000/1000 bootstrap replicates. B. Synteny analysis of vertebrate VEGF receptors in the human, mouse, chick, and zebrafish genome assemblies. Different classes in A and B are colored similarly. Dashed lines represent synteny breaks in the Flt4 loci. Brackets indicate previously suggested names.
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pgen-1000064-g001: Adapted from Bussmann et al., 2007 [4].A. Unrooted neighbor-joining tree of vertebrate VEGF receptors. Different colors represent different classes of VEGF receptors. Purple shading was used to highlight the fourth vertebrate VEGF receptor class, which is missing in eutherian mammals. The node representing this fourth class was supported in 1000/1000 bootstrap replicates. B. Synteny analysis of vertebrate VEGF receptors in the human, mouse, chick, and zebrafish genome assemblies. Different classes in A and B are colored similarly. Dashed lines represent synteny breaks in the Flt4 loci. Brackets indicate previously suggested names.

Mentions: In many cases, the presence of two zebrafish orthologues of a single human gene can be attributed to a whole-genome duplication event that occurred within the teleost lineage. It was therefore hypothesized that zebrafish contains duplicated KDR genes, which were consequently called kdra (the gene originally called flk1) and kdrb (the gene that is most similar to human KDR). However, two lines of evidence have recently challenged this view [4], [13]–[15] and rather suggest that this is a case of “ohnologs” [16],[17]. First, VEGF receptor sequences that were most similar to zebrafish flk1/kdra were identified, not only in the genomes of other teleosts, but also in the genomes of higher vertebrates, such as Xenopus, chicken, platypus, and opossum. Phylogenetic analysis of these genes, together with other VEGF receptor sequences, clearly showed that they cluster as a separate class (Figure 1A). Second, synteny analysis showed that the loci containing the zebrafish flk1/kdra and kdrb have been conserved throughout vertebrate evolution (Figure 1B), strongly indicating the presence of both genes in the common ancestor of fish and mammals and the loss of a fourth VEGF receptor in the eutherian lineage (after the divergence of marsupial and placental mammals).


Zebrafish VEGF receptors: a guideline to nomenclature.

Bussmann J, Lawson N, Zon L, Schulte-Merker S, Zebrafish Nomenclature Committ - PLoS Genet. (2008)

Adapted from Bussmann et al., 2007 [4].A. Unrooted neighbor-joining tree of vertebrate VEGF receptors. Different colors represent different classes of VEGF receptors. Purple shading was used to highlight the fourth vertebrate VEGF receptor class, which is missing in eutherian mammals. The node representing this fourth class was supported in 1000/1000 bootstrap replicates. B. Synteny analysis of vertebrate VEGF receptors in the human, mouse, chick, and zebrafish genome assemblies. Different classes in A and B are colored similarly. Dashed lines represent synteny breaks in the Flt4 loci. Brackets indicate previously suggested names.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2367445&req=5

pgen-1000064-g001: Adapted from Bussmann et al., 2007 [4].A. Unrooted neighbor-joining tree of vertebrate VEGF receptors. Different colors represent different classes of VEGF receptors. Purple shading was used to highlight the fourth vertebrate VEGF receptor class, which is missing in eutherian mammals. The node representing this fourth class was supported in 1000/1000 bootstrap replicates. B. Synteny analysis of vertebrate VEGF receptors in the human, mouse, chick, and zebrafish genome assemblies. Different classes in A and B are colored similarly. Dashed lines represent synteny breaks in the Flt4 loci. Brackets indicate previously suggested names.
Mentions: In many cases, the presence of two zebrafish orthologues of a single human gene can be attributed to a whole-genome duplication event that occurred within the teleost lineage. It was therefore hypothesized that zebrafish contains duplicated KDR genes, which were consequently called kdra (the gene originally called flk1) and kdrb (the gene that is most similar to human KDR). However, two lines of evidence have recently challenged this view [4], [13]–[15] and rather suggest that this is a case of “ohnologs” [16],[17]. First, VEGF receptor sequences that were most similar to zebrafish flk1/kdra were identified, not only in the genomes of other teleosts, but also in the genomes of higher vertebrates, such as Xenopus, chicken, platypus, and opossum. Phylogenetic analysis of these genes, together with other VEGF receptor sequences, clearly showed that they cluster as a separate class (Figure 1A). Second, synteny analysis showed that the loci containing the zebrafish flk1/kdra and kdrb have been conserved throughout vertebrate evolution (Figure 1B), strongly indicating the presence of both genes in the common ancestor of fish and mammals and the loss of a fourth VEGF receptor in the eutherian lineage (after the divergence of marsupial and placental mammals).

View Article: PubMed Central - PubMed

Affiliation: Hubrecht Laboratory (NIOB-KNAW NIOB), Utrecht, The Netherlands.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

In placental mammals (eutherians), there exist three paralogous genes of the vascular endothelial growth factor (VEGF) receptor family, namely FLT1 (also named VEGFR1), KDR (also named FLK1 and VEGFR2), and FLT4 (also named VEGFR3)... In the zebrafish, four genes encoding VEGF receptor proteins have been identified: the FLT1 orthologue ,, the FLT4 orthologue, and two genes with highest similarity to KDR/Flk1... However, the recent identification of a second potential KDR/FLK1 orthologue ,,, which in fact is more similar to the human gene, has caused confusion over the evolutionary relationships of zebrafish and mammalian VEGF receptors... It was therefore hypothesized that zebrafish contains duplicated KDR genes, which were consequently called kdra (the gene originally called flk1) and kdrb (the gene that is most similar to human KDR)... Second, synteny analysis showed that the loci containing the zebrafish flk1/kdra and kdrb have been conserved throughout vertebrate evolution (Figure 1B), strongly indicating the presence of both genes in the common ancestor of fish and mammals and the loss of a fourth VEGF receptor in the eutherian lineage (after the divergence of marsupial and placental mammals)... Although representing separate classes, experimental data revealed significant functional similarity of zebrafish flk1/kdra and kdrb... Furthermore, zebrafish VEGF can bind and activate both flk1/kdra and kdrb... Finally, flk1/kdra and kdrb genetically interact: knockdown of kdrb in a flk1/kdra mutant background resulted in similar phenotypes as those observed in embryos in which vegf was knocked down or in which a downstream signaling component, phospholipase-cγ1, is mutated ( and N... Lawson, unpublished data)... Therefore, to reflect that flk1/kdra is a prominent receptor in VEGF-A signaling in zebrafish, while at the same time indicating that it represents a fourth class of vertebrate VEGF receptors (and is not the result of a teleost gene duplication), we propose to rename this gene kdr-like... As the zebrafish kdrb gene is clearly orthologous to mammalian KDR, we propose to rename this gene kdr.

Show MeSH
Related in: MedlinePlus