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Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds

Author

Listed:
  • Aimée Zúñiga

    (Faculty of Biology, Utrecht University
    EMBL)

  • Anna-Pavlina G. Haramis

    (EMBL
    University College London)

  • Andrew P. McMahon

    (Molecular and Cellular Biology, Harvard University)

  • Rolf Zeller

    (Faculty of Biology, Utrecht University
    EMBL)

Abstract

Outgrowth and patterning of the vertebrate limb are controlled by reciprocal interactions between the posterior mesenchyme (polarizing region) and a specialized ectodermal structure, the apical ectodermal ridge (AER)1. Sonic hedgehog (SHH) signalling by the polarizing region modulates fibroblast growth factor (FGF)4 signalling by the posterior AER, which in turn maintains the polarizing region (SHH/FGF4 feedback loop)2,3. Here we report that the secreted bone-morphogenetic-protein (BMP) antagonist Gremlin4 relays the SHH signal from the polarizing region to the AER. Mesenchymal Gremlin expression is lost in limb buds of mouse embryos homozygous for the limb deformity (ld) mutation, which disrupts establishment of the SHH/FGF4 feedback loop5,6,7. Grafting Gremlin-expressing cells into ld mutant limb buds rescues Fgf4 expression and restores the SHH/FGF4 feedback loop. Analysis of Shh-null mutant embryos8,9 reveals that SHH signalling is required for maintenance of Gremlin and Formin (the gene disrupted by the ld mutations)10,11. In contrast, Formin, Gremlin and Fgf4 activation are independent of SHH signalling. This study uncovers the cascade by which the SHH signal is relayed from the posterior mesenchyme to the AER and establishes that Formin-dependent activation of the BMP antagonist Gremlin is sufficient to induce Fgf4 and establish the SHH/FGF4 feedback loop.

Suggested Citation

  • Aimée Zúñiga & Anna-Pavlina G. Haramis & Andrew P. McMahon & Rolf Zeller, 1999. "Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds," Nature, Nature, vol. 401(6753), pages 598-602, October.
    • Handle: RePEc:nat:nature:v:401:y:1999:i:6753:d:10.1038_44157
    DOI: 10.1038/44157
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    Cited by:

    1. Eriko Tsuboi & Satomi F. Ono & Ingrid Rosenburg Cordeiro & Reiko Yu & Toru Kawanishi & Makoto Koizumi & Shuji Shigenobu & Guojun Sheng & Masataka Okabe & Mikiko Tanaka, 2024. "Immobilization secondary to cell death of muscle precursors with a dual transcriptional signature contributes to the emu wing skeletal pattern," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Sofia Sedas Perez & Caitlin McQueen & Holly Stainton & Joseph Pickering & Kavitha Chinnaiya & Patricia Saiz-Lopez & Marysia Placzek & Maria A. Ros & Matthew Towers, 2023. "Fgf signalling triggers an intrinsic mesodermal timer that determines the duration of limb patterning," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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