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Inhibition of NF-κB activity results in disruption of the apical ectodermal ridge and aberrant limb morphogenesis

Nature volume 392, pages 615–618 (1998)Cite this article

Abstract

In Drosophila, the Dorsal protein establishes the embryonic dorso–ventral axis during development1. Here we show that the vertebrate homologue of Dorsal, nuclear factor-kappa B (NF-κB), is vital for the formation of the proximo–distal organizer of the developing limb bud, the apical ectodermal ridge (AER). Transcription of the NF-κB proto-oncogene c-rel is regulated, in part, during morphogenesis of the limb bud by AER-derived signals such as fibroblast growth factors. Interruption of NF-κB activity using viral-mediated delivery of an inhibitor results in a highly dysmorphic AER, reduction in overall limb size, loss of distal elements and reversal in the direction of limb outgrowth. Furthermore, inhibition of NF-κB activity in limb mesenchyme leads to a reduction in expression of Sonic hedgehog and Twist but derepresses expression of the bone morphogenetic protein-4 gene. These results are the first evidence that vertebrate NF-κB proteins act to transmit growth factor signals between the ectoderm and the underlying mesenchyme during embryonic limb formation.

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Figure 1: c-rel mRNA is expressed in discrete spatial and temporal patterns directed by AER-derived signals.
Figure 2: Sequestration of NF-κB activity leads to a reduction in limb outgrowth along both the proximo–distal and the antero–posterior axes.
Figure 3: Sequestration of NF-κB leads to a dysmorphic limb.
Figure 4: Inhibition of NF-κB activity results in a dysmorphic AER.
Figure 5: Inhibition of NF-κB activity leads to a reduction of Shh and Twist mRNA expression while derepressing BMP -4 gene expression.

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Acknowledgements

We thank B. L. M. Hogan, J. Barnett, C. Wright, D. Bader, L. Rollins-Smith, and members of the Kerr laboratory for helpful discussions and critical review of this manuscript. A.McMahon for avian Shh cDNA; B. Hogan for the M-Twist and Bmp-4 cDNA; C. B. Newgard for the adenoviral shuttle and wild-type vectors; S. Hughes for RCAS-BP(A) and RCAS-AlkPhos vectors; C.McCarther for the Fgf-8 cDNA; C. Tabin for cHoxA and cHoxD cDNA series. This work was supported by an NIH grant, the American Cancer Society, and gene therapy pilot funds from the Vanderbilt Cancer Center Grant and MSKCC Support Grant. P.B.B.is a predoctoral fellow supported by an NIH training grant. L.D.K. is a recipient of an ACS Junior Faculty Research Award and a Cancer Research Institute Investigator Award.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Nashville, 37232-2363, Tennessee, USA

    Paul B. Bushdid, Fiona E. Yull & Lawrence D. Kerr

  2. Department of Cell Biology, Nashville, 37232-2363, Tennessee, USA

    Dana M. Brantley, Gareth L. Blaeuer, Loren H. Hoffman & Lawrence D. Kerr

  3. Vanderbilt Cancer Center, Vanderbilt University School of Medicine, Nashville, 37232-2363, Tennessee, USA

    Lawrence D. Kerr

  4. Memorial Sloan-Kettering Cancer Center, Molecular Biology Program, New York, 10021, New York, USA

    Lee Niswander

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Bushdid, P., Brantley, D., Yull, F. et al. Inhibition of NF-κB activity results in disruption of the apical ectodermal ridge and aberrant limb morphogenesis. Nature 392, 615–618 (1998). https://doi.org/10.1038/33435

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