Direct and Long-Range Action of a DPP Morphogen Gradient

Nellen, Denise; Burke, Richard; Struhl, Gary; Basler, Konrad

doi:10.1016/s0092-8674(00)81114-9

Cited by 863 publications

(667 citation statements)

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“…eIF4A R321H and transgenic flies carrying UAS-eIF4A and UAS-eIF4A R321H were as described previously 1 . UAS-Tkv QD , UAS-Put DN and UAS-Sax DN were as described previously 13,18 . The Pelement-associated eIF4A alleles (eIF4A 1069 and eIF4A 1006 ) were as described previously 3 .…”

Section: Fly Stocks and Geneticsmentioning

confidence: 99%

A novel function of Drosophila eIF4A as a negative regulator of Dpp/BMP signalling that mediates SMAD degradation

2006

Nat Cell Biol

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Signalling by the TGF-β superfamily member and BMP orthologue Decapentaplegic (Dpp) is crucial for multiple developmental programmes and has to be tightly regulated. Here, we demonstrate that the Drosophila Dpp pathway is negatively regulated by eukaryotic translation initiation factor 4A (eIF4A), which mediates activation-dependent degradation of the Dpp signalling components Mad and Medea. eIF4A mutants exhibit increased Dpp signalling and accumulation of Mad and phospho-Mad. Overexpression of eIF4A decreases Dpp signalling and causes loss of Mad and phospho-Mad. Furthermore, eIF4A physically associates with Mad and Medea, and promotes their degradation following activation of Dpp signalling in a translationindependent manner. Finally, we show that eIF4A acts synergistically with, but independently of, the ubiquitin ligase DSmurf, indicating that a dual system controls SMAD degradation. Thus, in addition to being an obligatory component of the cap-dependent translation initiation complex, eIF4A has a novel function as a specific inhibitor of Dpp signalling that mediates the degradation of SMAD homologues.To understand the regulation of Dpp signalling, we have previously identified a dominantnegative mutation in eukaryotic translation initiation factor 4A (eIF4A), which acts as a suppressor of dpp haploinsufficiency 1 . This allele, eIF4A R321H (also known as eIF4A YE9 ), is associated with an increased number of amnioserosa cells 1 , the fate of which is determined by Dpp in the early Drosophila embryo 2 . To investigate whether eIF4A mutations cause increased Dpp signalling in general, we examined the effects of eIF4A mutations on Dpp signalling in other developmental or genetic contexts. First, we found that eIF4A R321H and eIF4A 1006 (a null allele 1,3 ) dominantly suppressed the sterility of females that were doubly heterozygous for null mutations of Mad and saxophone (sax) (see Methods), which encode homologues of mammalian Smad1/5/8 and type I activin receptor, respectively [4][5][6][7][8] AUTHOR CONTRIBUTIONSJ.L. coplanned the project, performed experiments and analysed data. W.X.L. planned the project and wrote the paper. COMPETING FINANCIAL INTERESTSThe authors declare that they have no competing financial interests.Reprints and permission information is available online at http://npg.nature.com/reprintsandpermissions/ Note: Supplementary Information is available on the Nature Cell Biology website. (Table 1). eIF4A R321H heterozygosity similarly enhanced the effects of overepxressing dpp by the eye-specific GMR-Gal4 (see below and Fig. 1h). Therefore, eIF4A mutations seem to augment the Dpp signalling strength. NIH Public AccessTo investigate at which step loss of eIF4A increases Dpp signalling, we examined the levels of active or phosphorylated Mad (pMad). In early wild-type embryos, pMad signals are detected in spatial and temporal patterns that are correlated with dpp expression 10 . At stage 10, pMad signals had dissipated from the procephalon and posterior midgut of wild-type embryos (...

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Section: Fly Stocks and Geneticsmentioning

confidence: 99%

A novel function of Drosophila eIF4A as a negative regulator of Dpp/BMP signalling that mediates SMAD degradation

2006

Nat Cell Biol

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“…Second, activin and TGF-␤1 are able to signal across layers of cells lacking receptors (Gurdon et al, 1994), indicating that these factors were not inducers of other morphogens and, therefore, were acting directly on cells at some distance from their source. Elegant genetic studies using receptorless cells had previously led to similar conclusions for Dpp (BMP4) and Wingless (Wnt) signaling in Drosophila (Nellen et al, 1996;Zecca et al, 1996;Lecuit et al, 1996). A weakness of the Xenopus studies is that they relied on the use of ligands and receptors (activin and TGF-␤1 and a TGF-␤ receptor) that are not expressed in the embryo.…”

Section: Establishment Of Morphogen Gradients Part I: Evidence For Dmentioning

confidence: 99%

Morphogen gradients, positional information, and Xenopus: Interplay of theory and experiment

Green

2002

Developmental Dynamics

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The idea of morphogen gradients has long been an important one in developmental biology. Studies with amphibians and with Xenopus in particular have made significant contributions to demonstrating the existence, identity, and mechanisms of action of morphogens. Mesoderm induction and patterning by activin, nodals, bone morphogenetic proteins, and fibroblast growth factors have been analyzed thoroughly and reveal recurrent and combinatorial roles for these protein growth factor morphogens and their antagonists. The dynamics of nodal-type signaling and the intersection of VegT and ␤-catenin intracellular gradients reveal detailed steps in early long-range patterning. Interpretation of gradients requires sophisticated mechanisms for sharpening thresholds, and the activin-Xbra-Gsc system provides an example of this. The understanding of growth factor signal transduction has elucidated growth factor morphogen action and provided tools for dissecting their direct longrange action and distribution. The physical mechanisms of morphogen gradient establishment are the focus of new interest at both the experimental and theoretical level. General themes and emerging trends in morphogen gradient studies are discussed.

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“…One situation in which the retardation of diffusion by PGs may be of particular biological value is in the establishment of gradients of signaling molecules within PG-rich extracellular matrices. During development, important gradients of several GAG-binding growth factors, such as BMPs, hedgehogs and Wnts are employed (Nellen et al, 1996;Zecca et al, 1996), and during both development and inflammation, gradients of GAG-binding chemotactic factors, such as netrins, semaphorins, hepatocyte growth factor and chemokines, seem to be important (Witt and Lander, 1994;Messersmith et al, 1995;Ebens et al, 1996;Serafini et al, 1996). Reductions in molecular diffusivity -such as would be brought about by the reversible binding of these molecules to PGs -can have interesting consequences for the shapes of the gradients that these molecules will form by simple diffusion.…”

Section: Beyond Catalysis Of Growth Factor-receptor Encounter: Generamentioning

confidence: 99%

Proteoglycans: Master regulators of molecular encounter?

Lander

1998

Matrix Biology

103

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Direct and Long-Range Action of a DPP Morphogen Gradient

Cited by 863 publications

References 56 publications

A novel function of Drosophila eIF4A as a negative regulator of Dpp/BMP signalling that mediates SMAD degradation

A novel function of Drosophila eIF4A as a negative regulator of Dpp/BMP signalling that mediates SMAD degradation

Morphogen gradients, positional information, and Xenopus: Interplay of theory and experiment

Proteoglycans: Master regulators of molecular encounter?

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