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Fgf8 signalling from the AER is essential for normal limb development

Nature Genetics volume 26, pages 460–463 (2000)Cite this article

Abstract

Vertebrate 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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Figure 1: Cre-mediated inactivation of Fgf8 in the limb bud.
Figure 2: Abnormalities in Shh expression in early stage Msx2-cre; Fgf8 limb buds.
Figure 3: Gene expression in Msx2-cre;Fgf8 limb buds.
Figure 4: Misregulation of Fgf4 in Msx2-cre;Fgf8 limb buds.
Figure 5: Skeletal abnormalities in Msx2-cre;Fgf8 limbs.

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Acknowledgements

We thank D. Duboule, Genetics Institute, R. Harland, B. Hogan, N. Itoh, A. McMahon and D. Ornitz for plasmids from which probes were prepared; M. Embry and Z. Serrano for technical assistance; and E. Meyers, T. Yamaguchi and our colleagues in the Martin laboratory for discussion and critical readings of the manuscript. X.S. was the recipient of a postdoctoral fellowship from the American Cancer Society. This work was supported by an HHMI Research Resources Program grant (76296-549901) to the UCSF School of Medicine and NIH grant RO1 HD34380 (to G.R.M.).

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  1. Mark Lewandoski

    Present address: Genetics of Vertebrate Development Section, Laboratory of Cancer and Developmental Biology, National Cancer Institute-FCRDC, Frederick, Maryland, USA

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  1. Department of Anatomy and Program in Developmental Biology, School of Medicine, San Francisco, California , USA

    Mark Lewandoski, Xin Sun & Gail R. Martin

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Correspondence to Gail R. Martin.

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Lewandoski, M., Sun, X. & Martin, G. Fgf8 signalling from the AER is essential for normal limb development . Nat Genet 26, 460–463 (2000). https://doi.org/10.1038/82609

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