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Derriére/Gdf-3 are all required for different aspects of mesoderm formation and
patterning. In mice, the Vg1 orthologues gdf1 and gdf3 are required for mesoderm
formation, suggesting that, unlike Activin, the role of Vg1 in mesoderm formation
may be conserved in mammals (Chu and Shen 2010 ).
7.6.4 Fibroblast Growth Factor in Frogs and Fish
There are 23 members of the Fibroblast Growth Factor (Fgf) family, grouped into
seven subfamilies based on their phylogeny: The Fgf1 Subfamily, Fgf4 Subfamily,
Fgf7 Subfamily, Fgf8 Subfamily, Fgf9 Subfamily, Fgf11 Subfamily, and the Fgf19
Subfamily (Itoh and Ornitz 2004 ). Many of these ligands and their cognate Receptor
Tyrosine Kinases are expressed during embryogenesis, which has presented a sig-
nificant challenge for biologists trying to decipher their functions. The first hint that
these proteins may have a role in mesoderm induction came when basic Fgf (bFgf/
Fgf2), a member of the Fgf1 Subfamily, was identified in a screen for purified
growth factors with the ability to induce mesoderm in Xenopus animal cap explants
(Slack et al. 1987 ). Low doses of purified bFgf/Fgf2 induce ventral mesoderm in
animal cap explants, while higher doses induce ventrolateral mesoderm (Slack et al.
1987 ; Kimelman and Maas 1992 ). bFgf/Fgf2 is not able to induce dorsal mesoderm.
By contrast, other growth factors tested in this screen were unable to induce meso-
derm even when used at very high, non-physiological concentrations. In frogs,
bFgf/Fgf2 is expressed both maternally and zygotically through the end of gastrula-
tion (Kimelman and Maas 1992 ). Fgf3, a member of the Fgf7 Subfamily, Fgf4 and
Fgf8 are also expressed in Xenopus embryos during gastrulation and can induce
mesoderm in animal cap explants (Isaacs et al. 1992 ; Tannahill et al. 1992 ; Christen
and Slack 1997 ; Lombardo et al. 1998 ; Hardcastle et al. 2000 ; Fletcher et al. 2006 ).
In zebrafish, Fgf2 and Fgf4 are expressed maternally and zygotically during gas-
trulation, while Fgf3 is expressed zygotically in the presumptive mesendoderm
(Phillips et al. 2001 ; Yamauchi et al. 2009 ; Lee et al. 2010 ). The zebrafish Fgf8 sub-
family consists of six genes, fgf8a, fgf8b (formerly fgf17a), fgf17 (formerly fgf17b),
fgf18a, fgf18b, and fgf24 (Itoh and Konishi 2007 ; Jovelin et al. 2007 ). Three of these
genes, fgf8a, fgf17, and fgf24 are co-expressed in the presumptive mesendoderm dur-
ing gastrulation (Reifers et al. 1998 ; Fischer et al. 2003 ; Cao et al. 2004 ). bFgf/Fgf2,
Fgf8a, or Fgf17 can all induce mesendoderm when overexpressed in embryos by
mRNA injection (Griffin et al. 1995 ; Reifers et al. 1998 ; Cao et al. 2004 ).
Trunk and tail mesoderm does not form in frog or zebrafish embryos in which Fgf
signaling is blocked by overexpression of a dominant negative mutant or by exposure
to an Fgf antagonist (Amaya et al. 1991 ; Griffin et al. 1995 ; Fletcher et al. 2006 ).
Interestingly, these embryos still form head mesoderm. Similar defects were reported
in medaka headfish (hdf) mutants, which are mutant for Fgfr-1 (Yokoi et al. 2007 ).
These results show that Fgf signaling is necessary and sufficient to specify certain types
of mesoderm in frogs. They also implicate Fgf ligands of four different subfamilies as
prime candidates for the ventral mesoderm-inducing signal predicted by the Three
Signal Model (Fig. 7.6b, yellow arrows) (Dale and Slack 1987b; Slack et al. 1987 ).
W. Tseng et al.