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BMP signals control limb bud interdigital programmed cell death by regulating FGF signaling.

Sangeeta Pajni-Underwood1, Catherine P Wilson, Cindy Elder

  • 1Laboratory of Cancer and Developmental Biology National Institutes of Health, Frederick, MD 21702, USA.

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Bone morphogenetic proteins (BMPs) indirectly regulate limb development by controlling fibroblast growth factors (FGFs) in the apical ectodermal ridge (AER). This regulation is crucial for programmed cell death (PCD) that removes webbing between digits.

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Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Genetics

Background:

  • Vertebrate limb development involves programmed cell death (PCD) to remove interdigital tissue.
  • Bone morphogenetic proteins (BMPs) are hypothesized to induce PCD, but the mechanism remains unclear.
  • Fibroblast growth factors (FGFs) act as cell survival factors, potentially mediating BMP effects.

Purpose of the Study:

  • To investigate the role of BMP signaling in the apical ectodermal ridge (AER) on interdigital PCD.
  • To determine if BMPs indirectly regulate PCD through FGFs.
  • To elucidate the genetic mechanisms controlling limb webbing development.

Main Methods:

  • Specific inactivation of the Bmpr1a gene in the mouse limb bud AER.
  • Analysis of AER formation and interdigital PCD in Bmpr1a mutant mice.
  • Generation of double and triple mutants involving Bmpr1a, Fgf4, and Fgf8 in the AER.

Main Results:

  • Inactivation of Bmpr1a in the AER after initiation led to upregulated Fgf4 and Fgf8, resulting in webbed limbs due to inhibited interdigital PCD.
  • Double and triple inactivation experiments revealed that elevated Fgf4 expression maintains webbing even when Bmpr1a and Fgf8 are inactivated.
  • Elimination of webbing was observed upon inactivation of Bmpr1a, Fgf8, and one copy of Fgf4.

Conclusions:

  • BMP signaling to the AER indirectly regulates interdigital PCD.
  • BMPs control AER-FGF expression, which in turn acts as a survival factor for interdigital mesenchyme.
  • This study provides genetic evidence for an indirect mechanism of BMP action in limb development.