Nature Genetics
26, 460 - 463 (2000)
doi:10.1038/82609
Fgf8 signalling from the AER is essential for normal limb development
Mark Lewandoski1, 2, Xin Sun1
& Gail R. Martin11
Department of Anatomy and Program in Developmental
Biology, School of Medicine, San Francisco, California
, USA. 2
Present address: Genetics of Vertebrate Development
Section, Laboratory of Cancer and Developmental Biology, National Cancer Institute-FCRDC
, Frederick, Maryland, USA.
Correspondence should be addressed to Gail R. Martin gmartin@itsa.ucsf.eduVertebrate limb development depends on signals from the apical ectodermal
ridge (AER), which rims the distal tip of the limb bud1. Removal
of the AER in chick results in limbs lacking distal skeletal elements2,
3. Fibroblast growth factor (FGF) proteins can substitute for the
AER (refs 4−7), suggesting that
FGF signalling mediates AER activity. Of the four mouse Fgf genes (Fgf4
, Fgf8, Fgf9, Fgf17) known to display AER-specific
expression domains within the limb bud (AER-Fgfs), only Fgf8 is expressed
throughout the AER. Moreover, Fgf8 expression precedes that of other
AER-Fgfs (refs 8−13),
suggesting that Fgf8 may perform unique functions early in limb development6,
7. In mice, loss of function of Fgf4 (refs
13,14), Fgf9 (D. Ornitz, pers.
comm.) or Fgf17 (ref. 15) has no effect
on limb formation. We report here that inactivating Fgf8 in early limb
ectoderm causes a substantial reduction in limb-bud size, a delay in Shh
expression, misregulation of Fgf4 expression, and hypoplasia or
aplasia of specific skeletal elements. Our data identify Fgf8 as the only
known AER-Fgf individually necessary for normal limb development, and provide
insight into the function of Fgf signalling from the AER in the normal outgrowth
and patterning of the limb.
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