Increasing Fgf4 expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss of Fgf8 function

被引:79
|
作者
Lu, PF
Minowada, G [1 ]
Martin, GR
机构
[1] Univ Calif San Francisco, Sch Med, Dept Anat, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Sch Med, Program Dev Biol, San Francisco, CA 94143 USA
[3] Case Western Reserve Univ, Sch Med, Univ Hosp Cleveland, Dept Med,Div Pulm & Crit Care Med, Cleveland, OH 44106 USA
来源
DEVELOPMENT | 2006年 / 133卷 / 01期
关键词
cutaneous syndactyly; FGF signaling; limb development; apical ectodermal ridge; SHH/FGF loop; interdigital programmed cell death; polydactyly; mouse;
D O I
10.1242/dev.02172
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
A major function of the limb bud apical ectodermal ridge (AER) is to produce fibroblast growth factors (FGFs) that signal to the underlying mesenchyme. Previous studies have suggested that of the four FGF genes specifically expressed in the mouse AER, Fgf8 is unique not only in its expression pattern, but also because it is the only such FGF gene that causes limb skeletal abnormalities when individually inactivated. However, when both Fgf8 and Fgf4 are simultaneously inactivated in the AER, the limb does not develop. One possible explanation for these observations is that although both of these FGF family members contribute to limb development, Fgf8 has functions that Fgf4 cannot perform. To test this hypothesis, we used a novel method to substitute Fgf4 for Fgf8 expression in the developing limb bud by concomitantly activating a conditional Fgf4 gain-of-function allele and inactivating an Fgf8 loss-of-function allele in the same cells via Cre-mediated recombination. Our data show that when Fgf4 is expressed in place of Fgf8, all of the skeletal defects caused by inactivation of Fgf8 are rescued, conclusively demonstrating that FGF4 can functionally replace FGF8 in limb skeletal development. We also show that the increase in FGF signaling that occurs when the Fgf4 gain-of-function allele is activated in a wild-type limb bud causes formation of a supernumerary posterior digit (postaxial polyclactyly), as well as cutaneous synclactyly between all the digits. These data underscore the importance of controlling the level of FGF gene expression for normal limb development.
引用
收藏
页码:33 / 42
页数:10
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