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WntD is a feedback inhibitor of Dorsal/NF-κB in Drosophila development and immunity

Nature volume 437, pages 746–749 (2005)Cite this article

Abstract

Regulating the nuclear factor-κB (NF-κB) family of transcription factors is of critical importance to animals, with consequences of misregulation that include cancer, chronic inflammatory diseases and developmental defects1. Studies in Drosophila melanogaster have proved fruitful in determining the signals used to control NF-κB proteins, beginning with the discovery that the Toll/NF-κB pathway, in addition to patterning the dorsal–ventral axis of the fly embryo, defines a major component of the innate immune response in both Drosophila and mammals2,3. Here, we characterize the Drosophila wntD (Wnt inhibitor of Dorsal) gene. We show that WntD acts as a feedback inhibitor of the NF-κB homologue Dorsal during both embryonic patterning and the innate immune response to infection. wntD expression is under the control of Toll/Dorsal signalling, and increased levels of WntD block Dorsal nuclear accumulation, even in the absence of the IκB homologue Cactus. The WntD signal is independent of the common Wnt signalling component Armadillo (β-catenin). By engineering a gene knockout, we show that wntD loss-of-function mutants have immune defects and exhibit increased levels of Toll/Dorsal signalling. Furthermore, the wntD mutant phenotype is suppressed by loss of zygotic dorsal. These results describe the first secreted feedback antagonist of Toll signalling, and demonstrate a novel Wnt activity in the fly.

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Figure 1: wntD is expressed with D–V polarity, and is under the control of Toll signalling.
Figure 2: Overexpression of WntD blocks Dorsal protein activation independently of Cactus.
Figure 3: wntD knockout flies exhibit ectopic Dorsal activation.
Figure 4: wntD mutants show an aberrant response to microbial infection.

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Acknowledgements

We thank J. Brown for preparing WntD protein for antibody production; C-H. Wu and K. Xu for preliminary experiments with wntD; M. Fish for p-element transformations; J. Sekelsky and K. Golic for fly strains and vectors used in gene targeting; S. Roth, G. Zimmermann and the Developmental Studies Hybridoma Bank for antibodies; A. O'Reilly and the Bloomington Stock Center for fly stocks; and C. Logan and A. Mikels for reading of the manuscript. M.D.G. was supported by a Howard Hughes Medical Institute predoctoral fellowship and a Stanford Graduate Fellowship. This work was supported by grants from the NIH to R.N. and D.S.S. and by the Howard Hughes Medical Institute.

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  1. Department of Developmental Biology, Howard Hughes Medical Institute, Beckman Center,

    Michael D. Gordon & Roel Nusse

  2. Department of Microbiology and Immunology, Stanford University School of Medicine, California, 94305, Stanford, USA

    Marc S. Dionne & David S. Schneider

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Correspondence to Roel Nusse.

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Supplementary Methods

A description of methods used in performing wnt8 gene disruption and producing Wnt8 antibodies. (DOC 26 kb)

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Gordon, M., Dionne, M., Schneider, D. et al. WntD is a feedback inhibitor of Dorsal/NF-κB in Drosophila development and immunity. Nature 437, 746–749 (2005). https://doi.org/10.1038/nature04073

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