WNT Signaling in D. melanogaster
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WNT Signaling in D. melanogaster
The development of tissues and organs in multicellular organisms is controlled by the interplay of several signaling pathways that cross talk to provide positional information and induce cell fate specification. Together with other families of secreted factors such as TGF-Betas (Transforming Growth Factor-Betas), FGFs (Fibroblast Growth Factors), Hedgehog and Notch proteins, WNT (Wingless-Type MMTV Integration Site Family) Growth Factors are crucially implicated in these processes. The WNT genes encode a large family of secreted protein growth factors that have been identified in animals from hydra to human. The name WNT denotes the relationship of this family to the Drosophila segment polarity gene Wg (Wingless) and to its vertebrate ortholog, Int1, a mouse protooncogene. At present, close to 100 Wnt genes have been isolated from various species. Drosophila contains seven WNT genes: WNT1/Wg (Wingless), WNT2, WNT4, WNT5, WNT6, WNT8 and WNT10. Of the seven Drosophila WNT genes, Wg is best studied (Ref.1).

WNT signals are transduced through three distinct intracellular signaling pathways including the canonical WNT/Ctnn-Beta (Beta-Catenin) pathway, the WNT/Ca2+ pathway, and the WNT/Polarity pathway (also called the PCP (Planar Cell Polarity) Pathway). The WNT/Ctnn-Beta pathway primarily regulates Cell fate determination during development, whereas the major function of the WNT/Polarity pathway is regulation of Cytoskeletal organization. The biological function of the WNT/Ca2+ pathway is unclear. In Drosophila, WNT/Beta-Catenin pathway has been well known whereas WNT ligand for Planar Cell Polarity pathway has not been identified (Ref.2).

Reception and transduction of WNT signals in WNT/Ctnn-Beta pathway in Drosophila involves binding of WNT protein Wg to members of two distinct families of cell-surface receptors, members of the Frizzled gene family, Fz (Frizzled) and Fz2 (Frizzled-2) and to LRP (LDL-Receptor-related Protein) family member Arr (Arrow). Fz and Fz2 are seven transmembrane proteins with cysteine-rich extracellular domains. In Drosophila, Wg is required during embryogenesis for segmental patterning, muscle development, and midgut formation and to specify appendage primordia. Porc (Porcupine), an ER (Endoplasmic Reticulum) associated transmembrane protein, functions in processing of Wg in the signaling cell. Wg binds to Fz and Fz2 and to Arr co-receptor, resulting in the activation of Dsh (Dishevelled) (Ref.3). Drosophila Dsh is a modular protein of unknown function that is well conserved in relation to its vertebrate homologs. It consists of three conserved domains. The first, a DIX (Dishevelled-Axin) domain, is similar to a domain in murine Axin. The second contains a PDZ (PSD95-Discs Large-ZO1) domain, which recognizes and binds short motifs at the carboxyl termini of proteins but may bind other motifs as well. PDZ domains can also form dimers. The third domain, called DEP (Dishevelled-EGL10-Pleckstrin), is conserved among a set of proteins that have in common the ability to regulate various GTPases, including both heterotrimeric G-Proteins and Ras-like small GTPases. DIX and PDZ domains signal to the canonical pathway. A mutation in the DEP domain impairs both membrane localization and the function of Dsh in Wnt/Polarity signaling, indicating that translocation is important for function (Ref.2 and Ref.4).

Dsh acts by binding to and inhibiting the Axin protein that negatively regulates Wg signaling. Axin is a scaffolding protein that binds to Apc (Apc-like), another negative regulator of Wg signaling, and to Arm (Armadillo), a homolog of Ctnn-Beta(Catenin-Beta). Axin negatively regulates Arm by facilitating the action of ZW3 (Zeste White-3)/ Sgg (Shaggy), a homolog of the vertebrate Serine/Threonine kinase GSK3-Beta (Glycogen Synthase Kinase-3-Beta). ZW3 phosphorylates Arm, leading to its destruction by the Ubiquitin pathway. Inhibition of ZW3 results in the stabilization of Arm. Stabilized Arm forms a complex with the HMG-box DNA-binding protein dTCF (Drosophila T-Cell Factor)/Pan (Pangolin) and activates transcription of Wg target genes. In the absence of Arm, Pan acts as a transcriptional repressor of Wg-responsive genes, and Gro (Groucho) acts as a co-repressor in this process. The products of two newly identified Drosophila segment polarity genes, Lgs (Legless), and Pygo (Pygopus) are required for WNT signal transduction at the level of nuclear Ctnn-Beta. Pygo is found in a complex with Arm and is required for dTCF-mediated transcription, but not for Wg-induced stabilization of Arm. Lgs links Pygo to Arm. Pygo effectively enhances the transcription of TCF reporter genes. The human and Drosophila Pygo proteins share two domains of structural similarity: the NHD (N-terminal Homology Domain) and the C-terminal PHD finger. The PHD finger mediates the binding of Pygo to the HD1 domain of Lgs. Binding leads to TCF mediated transcription via Arm. Wg is also required for the maintenance of Engrailed (En) synthesis. Recently discovered WNT target gene Nkd (Naked) functions as an antagonist for WNT signaling. Nkd protein binds to Dsh and blocks Ctnn-Beta pathway (Ref.5).

HSPGs (Heparan Sulphate Proteoglycans) are also important for signaling by WNT family members. The Drosophila HSPGs Dally (Division Abnormally Delayed) and Dally-Like are essential for Wg signaling and act either as co-receptors stabilizing the Wg/Frizzled complex or by restricting the extracellular diffusion of the ligand. Mutations in the Drosophila genes Sugarless (also called Kiwi and Suppenkasper) and Sulphateless, which encode homologues of UDP-Glucose dehydrogenase and N-deacetylase/ N-Sulphotransferase respectively, have revealed the necessity of these Glycosaminoglycan biosynthetic enzymes in Wg signaling. These proteins are needed for Heparan Sulphate modification of the co-receptors Dally and Dally-like. The Wg signaling pathway has been well studied in embryonic and larval development. In the embryo, Wg is involved in segmentation and patterning of the embryonic epidermis, and in the development of head structures, nervous system, midgut and malpighian tubules. During larval development, Wg is required for development of imaginal discs, in particular for dorso ventral patterning of the leg and wing, bristle specification, and eye development (Ref.6).