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Functions of FGF signalling from the apical ectodermal ridge in limb development

Abstract

To determine the role of fibroblast growth factor (FGF) signalling from the apical ectodermal ridge (AER), we inactivated Fgf4 and Fgf8 in AER cells or their precursors at different stages of mouse limb development. We show that FGF4 and FGF8 regulate cell number in the nascent limb bud and are required for survival of cells located far from the AER. On the basis of the skeletal phenotypes observed, we conclude that these functions are essential to ensure that sufficient progenitor cells are available to form the normal complement of skeletal elements, and perhaps other limb tissues. In the complete absence of both FGF4 and FGF8 activities, limb development fails. We present a model to explain how the mutant phenotypes arise from FGF-mediated effects on limb bud size and cell survival.

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Figure 1: Timing of Fgf4 and Fgf8 inactivation in hindlimb and forelimb buds.
Figure 2: Limb skeletal phenotypes.
Figure 3: AER morphology and gene expression in hindlimb buds.
Figure 4: Cell death and distribution of muscle cell precursors.
Figure 5: Cell proliferation and limb bud size.
Figure 6: A model for AER-FGF function in the limb.

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Acknowledgements

We thank M. Lewandoski, whose studies on the phenotype of Fgf8 single mutant embryos first suggested the model of AER-FGF function described here, for discussion at the outset of this work. We are grateful to J. Fallon, D. Kingsley and C. Tickle for discussion, and C. Tabin and A. Dudley for sharing unpublished information and helpful comments. We also thank D. Duboule, P. Gruss, R. Harland, B. Hogan, N. Itoh, J.-C. Izpisua-Belmonte, V. Lefebvre, A. McMahon, D. Ornitz, P. Sharpe, M. Scott and R. Wisdom for providing plasmids from which probes were prepared; D. Lakeland for help with statistical analysis; C. Larabell for technical advice on confocal microscopy; C. Petersen, Z. Serrano, J. Watanabe and R. Rantala for technical assistance; and H. Ingraham, J. Saunders, G. Schubiger and our colleagues in the Martin laboratory for comments on the manuscript. X.S. was the recipient of a postdoctoral fellowship from the American Cancer Society and was supported by an NIH Training grant. F.M. is the recipient of an individual National Research Service Award from the NIH. This work was supported by an HHMI Research Resources Program grant to the UCSF School of Medicine, and an NIH grant to G.R.M.

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Correspondence to Gail R. Martin.

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Sun, X., Mariani, F. & Martin, G. Functions of FGF signalling from the apical ectodermal ridge in limb development. Nature 418, 501–508 (2002). https://doi.org/10.1038/nature00902

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