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First published online January 11, 2008
doi: 10.1242/10.1242/dev.000505

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Wnt/Notch signalling and information processing during development

Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.

View larger version (4K): [in this window] [in a new window]   Fig. 1. Information and signal transduction. The term `signal transduction', as used in cell biology, initially arose as an analogy with the transmission of information in telecommunications (Rodbell, 1995). In telecommunications, a channel is used to transduce information from a source to a specific destination. A transmitter places the information into the channel and a receiver picks it up and delivers it to the destination. In biological systems, the signal is the source, and the targets the destination. The signal transduction system is the channel that is accessed through a receptor. The system's effector acts as the receiver and delivers the signal to the targets. In telecommunications, noise is an inherent property of the transduction process. Noise exists in the source and destination, but most significantly in the channel, which has to pass the information between the transmitter and the receiver. It is highly unlikely that biological signal transduction is immune to noise.

View larger version (66K): [in this window] [in a new window]   Fig. 2. The spatial and functional organization of the core mechanism of Wnt/β-catenin signalling. (A) In the absence of ligand, a destruction complex assembles around the scaffolding protein Axin (see C for details), which binds and then labels β-catenin for proteolysis via phosphorylation of specific residues at its N-terminus. (B) Wnt binds to Frizzled (a) and triggers signalling by initiating a chain of events, which at a biochemical level are not well characterized. At the cell surface, the Wnt-Frizzled complex forms a trimeric complex with LRP5/6 (Arrow in Drosophila) and this triggers the activity of Dishevelled (Dsh), which promotes the association of the destruction complex with the LRP5/6-Frizzled complex (b,c). A chain of events (detailed in C) leads to the LRP5/6-mediated degradation of Axin (d) and the release of β-catenin from Axin (e). Free hypophosphorylated β-catenin can then enter the nucleus (f), where it nucleates a transcription modulator complex around TCF. (C) Structure and function of the Axin-based destruction complex. In the absence of Wnt, the complex is assembled and can bind β-catenin, which is then phosphorylated by GSK3β. Phosphorylated β-catenin is targeted for ubiquitination and proteasomal degradation. In the presence of Wnt, the destruction complex is recruited to the cell surface, where a series of phosphorylation events results in the degradation of Axin and the release of β-catenin. For further details, see text and published literature (Logan and Nusse, 2004; Tolwinski and Wieschaus, 2004b). APC, Adenomatous polyposis coli; β-TrCP, β-transducin repeat-containing protein (also known as Ebi); CKI, Casein kinase; DSH, Dishevelled; CtBP, C-terminal-binding protein; GSK3β, Glycogen synthase kinase 3β; Lgs, Legless; LRP, Low density lipoprotein receptor-related protein; Pol II, RNA polymerase II; PP2A, Protein phosphatase 2A; TCF, T cell factor (also known as Pangolin); Ub, ubiquitination.

View larger version (43K): [in this window] [in a new window]   Fig. 3. Structure and functional organization of Notch signalling. Notch and its ligands (members of the DSL family) are transmembrane proteins. (A) In the absence of ligand, the full-length Notch protein is present at the cell surface as a heterodimer of the extracellular (ECN) and the transmembrane-intracellular domains. (B) (a) Binding of a Notch ligand (Serrate/Jagged/Delta) to specific EGF-like repeats (blue) triggers (b) a proteolytic cleavage, S2, in the extracellular juxtamembrane region (grey) of Notch by members of the ADAM tumour necrosis factor converting enzyme (TACE) proteases. This event primes (c) a second ligand-independent cleavage, S3, within the transmembrane domain (purple) of Notch, which is catalysed by the Presenilin--secretase complex. As a result of S3 cleavage, (d) the intracellular domain of Notch (NICD) enters the nucleus, where it (e) interacts with CSL, displaces co-repressors and through Mastermind (MAML) recruits co-activators to (f) promote the transcription of target genes. For further details, see text and published literature (Bray, 2006; Ehebauer et al., 2006; Kopan, 2002; Le Borgne, 2006). ADAM, a disintegrin and metalloprotease; CBP, CREB binding protein (also known as Crebbp); CSL, CBF/Suppressor of Hairless/LAG-1; DSL, Delta/Serrate/LAG-2; ECN, Extracellular Notch; Pol II, RNA polymerase II; TACE, TNF-converting enzyme.

View larger version (56K): [in this window] [in a new window]   Fig. 4. Functional networking of Wnt and Notch signalling during Drosophila wing development. During wing primordium patterning and sensory organ precursor (SOP) specification, the Wingless and Notch pathways act in a dynamic signalling landscape that endows cells with identity and orientation. The images to the left and right show wingless (wglacZ) expression in the epidermis of two wing discs at very early (left) and mid-third (right) instar. The white line straddling the middle of the Wingless stain represents the primordium of the wing margin (wm). Throughout the figure, ventral (V) is orientated down, dorsal (D) up, posterior (P) to the left and anterior (A) to the right. (A) Schematic of a wing disc between the first and second larval instars. Wing development is initiated at the intersection of the AP and DV boundaries by the joint activity of Notch and Wingless signalling. (B) During the transition from second to third instar, the DV boundary is established through the activity of Notch signalling triggered, initially, by the asymmetrically localized Notch ligands Serrate (Ser, dorsal, yellow) and Delta (Dl, ventral, red) that lead to the activation of wingless expression (blue) in a wide domain with a peak in the middle. This domain becomes progressively restricted to the DV boundary through an autoinihibitory effect of Wingless on its own expression. (C) Serrate and Delta are targets of Notch signalling, and Wingless signalling can contribute to this activation (arrows). As a result, a pattern emerges (D) of symmetric expression of Delta and Serrate (orange) and of Wingless (Wg, blue) at the DV boundary. This combination of events (B-D) leads to the formation and definition of the DV compartment boundary and its maintenance through a feedback loop in which Wingless maintains the expression of Serrate and Delta, which in turn maintain the expression of Wg. (E-G) As the third instar develops, the peripheral nervous system emerges (E). At the wing margin, it appears around the DV boundary within the domain of Delta and Serrate expression. In the second half of the third instar, high levels of Wingless signalling (blue) lead to the expression of proneural genes, such as senseless and members of the Achaete/Scute family (pink in F), which promote the appearance of SOPs (red in G). Notch-mediated lateral inhibition generates the spaced precursors that express high levels of AS-C and that will develop into sensory organs.

View larger version (9K): [in this window] [in a new window]   Fig. 5. Integration of prepatterning and lateral inhibition functions via Wnt and Notch signalling in Drosophila. In the epidermis of the imaginal disc of Drosophila, a combination of history and spatial patterning delimits clusters of cells (shown at the bottom) that can undergo neural specification through the expression of members of the Achaete-Scute complex (AS-C, blue). (A) AS-C expression is promoted by Wingless signalling and is antagonized by Notch (see text for details) in a manner that is independent of its transcriptional effector, Suppressor of Hairless [Su(H)], but depends on the activity of the ubiquitin ligase Deltex. (B) The binding of Wingless to its receptor complex triggers the activation of Armadillo/β-catenin and the suppression of the antagonistic activity of Notch, probably via Dishevelled. In consequence, all cells within the proneural cluster begin to express members of the AS-C. (C) One cell in the cluster (darker blue) begins to express higher levels of AS-C proteins than the other cells and, as a consequence, takes the lead in the process of `lateral inhibition', by which Notch signalling via Delta leads to the generation of free NICD and through Su(H) represses the expression of the AS-C genes.

View larger version (13K): [in this window] [in a new window]   Fig. 6. Wnt and Notch signalling in binary cell-fate decisions. (A) Pluri- or multipotent stem cell populations self-renew and differentiate. In the case of multipotent cells, stem cells are rare, self-renew infrequently and when they differentiate, they do so into an amplifying cell population, often called a transit-amplifying (TA) compartment. Ample evidence links Wnt signalling (red) to self-renewal and Notch signalling (blue) to TA cell population maintenance (see text and Table 1 for details). (B) A different mode of differentiation is characteristic of progenitor cells that can differentiate into one of two fates. Wnt and Notch signalling often act as permissive signals for either of the alternative fates. Under appropriate differentiation conditions, embryonic stem cells behave like progenitors and also have a binary option between neuroectoderm and endomesoderm (see Table 1). (C) In the vertebrate intestine, Wnt signalling promotes a stem cell fate, whereas Notch signalling is essential for the TA fate. TA cells can then differentiate into either of two fates, absorptive and secretory, that depend on Wnt or Notch signalling, respectively. It is possible that the activity of one pathway involves the repression of the other (see also Table 1).

View larger version (6K): [in this window] [in a new window]   Fig. 7. Wntch as a transistor for cell fate assignments. Interactions between Wnt and Notch signalling occur at two levels, as indicated by the two colours. A conserved functional network, in which β-catenin activity leads to the expression of the Notch DSL ligands, is observed in many instances, suggesting that β-catenin acts as an element of a network motif (see text for details). Less often, Notch signalling can lead to the activation of Wnt proteins and antagonists, and so can modulate Wnt signalling (dashed line). This transcriptional circuit, or elements of it, can be found in many developmental contexts. In addition, studies in Drosophila have revealed that the two pathways mutually antagonise each other at the level of signal transduction (blue box). The two coloured boxes indicate the two modules that connect the two systems interlocking them into a single functional unit. Interestingly, the blue box has a much shorter time scale than the yellow one, and therefore can influence it. As a whole, the system is a unit that can be `plugged' into different processes.

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