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Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development

Nature Geneticsvolume 25pages8386 (2000) | Download Citation



Development of the vertebrate limb bud depends on reciprocal interactions between the zone of polarizing activity (ZPA) and the apical ectodermal ridge1 (AER). Sonic hedgehog (SHH) and fibroblast growth factors (FGFs) are key signalling molecules produced in the ZPA and AER, respectively1,2. Experiments in chicks suggested that SHH expression in the ZPA is maintained by FGF4 expression in the AER, and vice versa3,4, providing a molecular mechanism for coordinating the activities of these two signalling centres. This SHH/FGF4 feedback loop model is supported by genetic evidence showing that Fgf4 expression is not maintained in Shh−/− mouse limbs5. We report here that Shh expression is maintained and limb formation is normal when Fgf4 is inactivated in mouse limbs, thus contradicting the model. We also found that maintenance of Fgf9 and Fgf17 expression is dependent on Shh, whereas Fgf8 expression is not. We discuss a model in which no individual Fgf expressed in the AER (AER–Fgf) is solely necessary to maintain Shh expression, but, instead, the combined activities of two or more AER–Fgfs function in a positive feedback loop with Shh to control limb development.

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We thank W. Skarnes for providing CGR8 ES cells; A. Nagy for providing the Z/AP reporter line; C. Chiang for providing Shh+/− mice; R. Harland (gremlin), Genetics Institute (Bmp2, Bmp4), N. Itoh (Fgf10, Fgf17), A. McMahon (Shh) and D. Ornitz (Fgf9) for providing plasmids; M. Embry and C. Petersen for technical assistance; and our colleagues in the Martin laboratory for helpful discussion and critical readings of the manuscript. X.S. is the recipient of a postdoctoral fellowship from the American Cancer Society. E.N.M. is the recipient of Mentored Clinical Scientist Development Award HD01216 from the NIH. This work was supported by an HHMI Research Resources Program grant (76296-549901) to the UCSF School of Medicine, and NIH grants RO1 DE12450 (to R.E.M.) and RO1 HD34380 (to G.R.M.).

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

    • Xin Sun
    • , Mark Lewandoski
    • , Erik N. Meyers
    •  & Gail R. Martin
  2. Department of Biochemistry and Molecular Biology, USC/Norris Cancer Center, Los Angeles, California, USA

    • Yi-Hsin Liu
    •  & Robert E. Maxson Jr


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Correspondence to Gail R. Martin.

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