Four FGF genes are expressed in the AER:
Fgf4
,
Fgf8
,
Fgf9
and
Fgf17
. To assess how these factors contribute to P–D patterning, the phenotype of the forelimb was examined in several FGF gene mutant combinations. The limb skeletal pattern of Fgf4;9,17 triple-knockout mutants was indistinguishable from wild type — an unexpected finding that revealed that Fgf8 is sufficient for normal limb development. Does this mean that the other three FGF genes are functionally redundant? Knocking out Fgf8 plus one or more of the other three FGF alleles generated a series of phenotypes with increasing severity — a finding that suggested that all four FGFs produced by the AER can contribute in the same way to limb patterning, but each to a different degree. By analysing both the skeletal phenotypes and the strength of FGF signalling, the relative contribution made by each FGF gene to limb development could be assessed — with Fgf8 contributing the most, followed by Fgf4, Fgf9, and then Fgf17.
The conclusion that FGFs are instructive for distal cell fates was reached by following the expression of
Meis1
, a homeobox transcription factor that is expressed in the proximal portion of the limb bud and that has been proposed to be involved in proximal specification. Because there is a stage at which mutant limb buds with progressively less FGF signalling are of the same size, the effect of reducing FGF signalling on limb P–D patterning could be determined. As FGF signalling was reduced, the Meis1-positive proximal domain occupied a greater proportion of the limb bud, whereas the Meis1-negative distal domain occupied a smaller proportion. Thus, the authors conclude that FGF signalling 'instructs' the P–D pattern of gene expression during limb development.
This is a preview of subscription content, access via your institution
