Direct and Long-Range Action of a Wingless Morphogen Gradient

Zecca, Myriam; Basler, Konrad; Struhl, Gary

doi:10.1016/s0092-8674(00)81991-1

Cited by 713 publications

(637 citation statements)

References 64 publications

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“…Studies of other morphogen signalling pathways indicate that each pathway culminates in the post-translational regulation of the activity of a single transcription factor or family of related transcription factors that have overlapping functions. For example, a constitutively active form of ␤-catenin/Armadillo (Arm), the transcriptional mediator of Wg signalling, is sufficient to induce the expression of both short range and long targets of Wg signalling in the Drosophila wing disc (Zecca et al, 1996). Similarly, Smad1 and Smad2, the mediators of Bmp4 and activin signalling, respectively, are sufficient to transduce the graded responses to these signals (Wilson et al, 1997;Shimizu and Gurdon, 1999).…”

Section: Signalling Pathways Are Linearmentioning

confidence: 99%

The interpretation of morphogen gradients

Ashe

Briscoe²

2006

Development

452

381

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DEVELOPMENT 385Morphogens act as graded positional cues that control cell fate specification in many developing tissues. This concept, in which a signalling gradient regulates differential gene expression in a concentration-dependent manner, provides a basis for understanding many patterning processes. It also raises several mechanistic issues, such as how responding cells perceive and interpret the concentration-dependent information provided by a morphogen to generate precise patterns of gene expression and cell differentiation in developing tissues. Here, we review recent work on the molecular features of morphogen signalling that facilitate the interpretation of graded signals and attempt to identify some emerging common principles. IntroductionThe transformation of the spatial distribution of naïve cells in a developing tissue into an organised arrangement of cell differentiation is fundamental to the development of multicellular organisms. More than a century ago, evidence began to accumulate that cells receive 'positional information' that instructs them to develop in specific ways, depending on their location within a tissue (Wolpert, 1996). Over the intervening decades, the potential for signalling gradients to provide this positional information has become a much-investigated and -debated subject, and the term 'morphogen' has been coined to describe such signals. Today the morphogen concept continues to form the basis of many models of pattern formation (Lewis et al., 1977;Green and Smith, 1991;Gurdon and Bourillot, 2001;Tabata and Takei, 2004). Typically, in current models it is proposed that a signal produced from a defined localised source forms a concentration gradient as it spreads through surrounding tissue (Fig. 1A). The graded signal then acts directly on cells, in a concentration-dependent manner, to specify gene expression changes and cell fate selection. Thus, the concentration of ligand provides cells with a measure of their position relative to the source of the signal and organises the pattern of cell differentiation. Experimental evidence from tissues in both vertebrates and invertebrates indicates that several molecules appear to function as graded signals. The roles of these signals range from the establishment of the initial polarities of embryos to specification of cell identity in specific tissues, notably limb appendages and the nervous system in both vertebrates and Drosophila. The examples we focus on in this review are introduced in Fig. 1. Evidence in support of these signals acting as graded morphogens has been summarised in recent reviews (Gurdon and Bourillot, 2001;Tabata and Takei, 2004).Although the morphogen concept has provided an enduring and valid framework for understanding pattern formation, it raises many mechanistic issues. Much attention has focused on how the distribution of a morphogen through a tissue establishes and maintains a gradient of activity (Vincent and Dubois, 2002;Tabata and Takei, 2004); however, how the signal is perceived and interpreted in a grad...

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Section: Signalling Pathways Are Linearmentioning

confidence: 99%

The interpretation of morphogen gradients

Ashe

Briscoe²

2006

Development

452

381

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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%