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Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning

Nature Genetics volume 34, pages 303–307 (2003)Cite this article

Abstract

During limb outgrowth, signaling by bone morphogenetic proteins (BMPs) must be moderated to maintain the signaling loop between the zone of polarizing activity (ZPA) and the apical ectodermal ridge (AER). Gremlin, an extracellular Bmp antagonist, has been proposed to fulfill this function and therefore be important in limb patterning. We tested this model directly by mutating the mouse gene encoding gremlin (Cktsf1b1, herein called gremlin). In the mutant limb, the feedback loop between the ZPA and the AER is interrupted, resulting in abnormal skeletal pattern. We also show that the gremlin mutation is allelic to the limb deformity mutation (ld). Although Bmps and their antagonists have multiple roles in limb development, these experiments show that gremlin is the principal BMP antagonist required for early limb outgrowth and patterning.

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Figure 1: Targeting of the gremlin locus.
Figure 2: Serial skeletal stains of embryos and newborn pups.
Figure 3: Shh–Fgf feedback loop analysis.
Figure 4: BMPs and BMP-target genes.
Figure 5: Expression of Fmn and complementation of ld with gremlin.

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Acknowledgements

The authors thank D. Strong for mouse husbandry; W. Skarnes for help with producing the gremlin mutant mouse; T. Grammer and J. Wallingford for comments on the manuscript; and A. McMahon, G. Martin, J. Hebert, M. Scott, P. Sharpe, R. Zeller and S. Dymecki for reagents and useful discussions. M.K.K. was supported by the Pediatric Scientist Development Program of the National Institute of Child Health and Human Development and a K08 award from the National Institute of Child Health and Human Development /National Institutes of Health. D.H. was supported by a career development award from the Muscular Dystrophy Association. R.M.H is supported by the National Institutes of Health, and the Muscular Dystrophy Association.

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Author notes

  1. David Hsu

    Present address: Renovis, 270 Littlefield Avenue, South San Francisco, California, 94080, USA

  2. Marc S Dionne

    Present address: Department of Microbiology and Immunology, Stanford University, California, 94305, USA

  3. Mustafa K Khokha and David Hsu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Cell Biology, University of California-Berkeley, 401 Barker Hall, Berkeley, 94720, California, USA

    Mustafa K Khokha, David Hsu, Lisa J Brunet, Marc S Dionne & Richard M Harland

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Correspondence to Richard M Harland.

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Khokha, M., Hsu, D., Brunet, L. et al. Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning. Nat Genet 34, 303–307 (2003). https://doi.org/10.1038/ng1178

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