discs large 1: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References
Gene name - discs large 1

Synonyms -

Cytological map position - 10B8

Function - links septate junctions to cytoskeleton

Key words - cytoskeleton - septate junctions - imaginal discs, asymmetric cell division, apical/basal polarity, tumor suppressor

Symbol - dlg1

FlyBase ID: FBgn0001624

Genetic map position - 1-34.8

Classification - Guanylate kinase signature and Src homology 3 (SH3) domain

Cellular location - cytoplasmic



NCBI links: Precomputed BLAST | Entrez Gene

Recent literature
Zandany, N., Marciano, S., Magidovich, E., Frimerman, T., Yehezkel, R., Shem-Ad, T., Lewin, L., Abdu, U., Orr, I. and Yifrach, O. (2015). Alternative splicing modulates Kv channel clustering through a molecular ball and chain mechanism. Nat Commun 6: 6488. PubMed ID: 25813388
Summary:
Ion channel clustering at the post-synaptic density serves a fundamental role in action potential generation and transmission. This study shows that interaction between the Shaker Kv channel and the PSD-95 scaffold protein underlying channel clustering is modulated by the length of the intrinsically disordered C terminal channel tail. It was further shown that this tail functions as an entropic clock that times PSD-95 binding. A 'ball and chain' mechanism is proposed to explain Kv channel binding to scaffold proteins, analogous to the mechanism describing channel fast inactivation. The physiological relevance of this mechanism is demonstrated in that alternative splicing of the Shaker channel gene to produce variants of distinct tail lengths resulted in differential channel cell surface expression levels and clustering metrics that correlate with differences in affinity of the variants for PSD-95. It is suggested that modulating channel clustering by specific spatial-temporal spliced variant targeting serves a fundamental role in nervous system development and tuning.

Liu, M., Li, Y., Liu, A., Li, R., Su, Y., Du, J., Li, C. and Zhu, A. J. (2016). The exon junction complex regulates the splicing of cell polarity gene dlg1 to control Wingless signaling in development. Elife 5. PubMed ID: 27536874
Summary:
Wingless (Wg)/Wnt signaling is conserved in all metazoan animals and plays critical roles in development. The Wg/Wnt morphogen reception is essential for signal activation, whose activity is mediated through the receptor complex and a scaffold protein Dishevelled (Dsh). This study reports that the exon junction complex (EJC) activity is indispensable for Wg signaling by maintaining an appropriate level of Dsh protein for Wg ligand reception in Drosophila. Transcriptome analyses in Drosophila wing imaginal discs indicate that the EJC controls the splicing of the cell polarity gene discs large 1 (dlg1), whose coding protein directly interacts with Dsh. Genetic and biochemical experiments demonstrate that Dlg1 protein acts independently from its role in cell polarity to protect Dsh protein from lysosomal degradation. More importantly, human orthologous Dlg protein is sufficient to promote Dvl protein stabilization and Wnt signaling activity, thus revealing a conserved regulatory mechanism of Wg/Wnt signaling by Dlg and EJC.
Xiong, X.P., Kurthkoti, K., Chang, K.Y., Li, J.L., Ren, X., Ni, J.Q., Rana, T.M. and Zhou, R. (2016). miR-34 modulates innate immunity and ecdysone signaling in Drosophila. PLoS Pathog 12: e1006034. PubMed ID: 27893816
Summary:
microRNAs are endogenous small regulatory RNAs that modulate myriad biological processes by repressing target gene expression in a sequence-specific manner. This study shows that the conserved miRNA miR-34 regulates innate immunity and ecdysone signaling in Drosophila. miR-34 over-expression activates antibacterial innate immunity signaling both in cultured cells and in vivo, and flies over-expressing miR-34 display improved survival and pathogen clearance upon Gram-negative bacterial infection; whereas miR-34 knockout animals are defective in antibacterial defense. In particular, miR-34 achieves its immune-stimulatory function, at least in part, by repressing the two novel target genes Dlg1 and Eip75B. In addition, there exists a mutual repression between miR-34 expression and ecdysone signaling, and miR-34 acts as a node in the intricate interplay between ecdysone signaling and innate immunity. Lastly, the cis-regulatory genomic elements and trans-acting transcription factors required for optimal ecdysone-mediated repression of miR-34 were identified. Taken together, these data enrich the repertoire of immune-modulating miRNAs in animals, and provide new insights into the interplay between steroid hormone signaling and innate immunity.


BIOLOGICAL OVERVIEW

Discs large (DLG) is the prototypic member of a growing family of proteins collectively termed membrane-associated guanylate kinase homologs (MAGUKs). DLG is required for septate junction structure, cell polarity, and proliferation control in Drosophila epithelia. Two other Drosophila MAGUK proteins are Dishevelled (involved in segment polarity) and Canoe (involved in Notch signaling).

Other molecules found at septate junctions include the cell adhesion protein Fasciclin III, as well as Expanded, and Coracle. Both Expanded and Coracle are members of the 4.1 family of proteins that includes mammalian ezrin, radixin and moesin. The 4.1 family proteins physically bind cytoskeletal elements. The protein Neurexin is a transmembrane component of septate junctions interacting with Coracle. Neurexin is required for septate junction and blood-nerve barrier formation and function (Baumgartner, 1996).

All MAGUKs contain a series of domains: either one or three copies of an 80-90 amino acid motif called DHR/PDZ (DLG Homologous Region/PSD-95), DLG, ZO-1, and a region with high similarity to guanylate kinases (GUK). Both the DHR/PDZ and the SH3 domains may serve as sites for protein-protein interactions. The subfamily of MAGUKs (DLG-R) includes DLG, as well as mammalian tight-junction proteins ZO-1 and ZO-2 (homologs of Drosophila Polychaetoid). In DLG-R family members there are three DHR/PDZ domains, each with a three-amino acid deficiency in the ATP binding site within the GUK, making unlikely the existence of guanylate kinase catalytic activity (Woods, 1996 and references).

Imaginal disc cells mutant for dlg lack apicobasal polarity and septate junctions. However, the adherens junctions (see Shotgun and Armadillo) are still present: in fact, adherens junctions can be found at various ectopic positions on mutant cell membranes. The dependence of septate junction structure on functional DLG is seen more clearly in the salivary gland, a differentiated epithelial tissue that grows during larval life by cell enlargement rather than by proliferation. Mutant salivary gland cells still have obvious apicobasal polarity, but the septate junctions (usually extending a long distance over the lateral cell membrane) are reduced to a small fraction of their normal length (Woods, 1996).

Both microfilament and microtubule networks are disrupted by loss of the DLG protein. Filamentous actin, enriched at the apical end of the cell in wild-type epithelia, is found throughout the cell in mutants. Organization of tubulin is also severly disrupted. After the loss of the DLG protein, septate junctions of imaginal discs and some larval epithelia show a drastic alterantion in distribution of Coracle and Expanded (two proteins of the band 4.1 family of membrane cytoskeletal proteins). Loss of the DLG protein results in the distribution of COR and EX throughout the cell. In proventriculus cells both COR and EX are normally highly localized at the apicolateral membrane, presumably at the position of the septate junctions. In mutants, nearly all the COR protein is lost rather than mislocalized (Woods, 1996).

Loss of Discs large also affects the distribution of Fasciclin III and neuroglian, two transmembrane proteins thought to be involved in cell adhesion. Fasciclin III is highly enriched at the septate junction and present in lower amounts in the lateral cell membrane, but is excluded from the adherens junction. Neuroglian is enriched at the apical end of the cell, reduced in the septate junction, and also reduced on the rest of the lateral cell membrane. Localization of FAS III and Neuroglian in both salivary glands and imaginal discs is dependent of DLG. When septate junctions are completely eliminated in dlg mutants, both proteins are found apparently unrestricted along the cell membrane. In fact Neuroglian appears to have an elevated level of expression compared with wild type, while FAS III levels are reduced (Woods, 1996).

The adherens junction has long been the darling of Drosophila research: one component (Armadillo) is a downstream target of wingless signals while another component (Shotgun, or Drosophila E-cadherin) is involved in homophylic cell adhesion. The septate junction of Drosophila, present in lieu of the tight junction of vertebrates, now rightly deserves more attention. Tight junctions in vertebrates are physically more closely associated with the adherens junction, but in Drosophila, septate junctions assume a more basolateral position. Five components are now associated with septate junctions, FAS III, Neuroglian, DLG, COR and EX. Mutation of DLG disrupts this association, suggesting a central role for DLG in tight junction stucture. DLG mutants show an enhanced level of disc cell proliferation, suggesting a role for the tight junction in regulation of cell growth (Woods, 1996). The recent finding that a vertebrate DLG homolog, ZO-1, undergoes nuclear localization at the site of wounding, suggests a role for MAGUK proteins in nuclear signaling (Gottardi, 1996).

An important function of MAGUK proteins appears to be conserved between flies and mammals. MAGUK proteins are present in synapses and are important in directing synapse structure. Chapsyn-110 and PSD-95, two mammalian MAGUK proteins, interact at postsynaptic sites to form a multimeric scaffold for the clustering of N-methyl-D-aspartate (NMDA) receptors and Shaker K+ channel subunits (Kim, 1996). Drosophila DLG is expressed at type I glutamatergic synapse of the neuromuscular junction and is associated with both presynaptic and postsynaptic membranes. Type Ib boutons are large and are filled with 40 nm clear vescles thought to contain glutamate. At the postsynaptic site, type Ib boutons are surrounded by an elaborate system of membranes, the subsynaptic reticulum (SSR), a postsynaptic specialization at these synapses. Mutations in dlg alter the expression of dlg and cause striking changes in the structure of the subsynaptic reticulum (Lahey, 1994).

The SSR consists of highly elaborated junctional membranes that surround Type I boutons. Hypomorphic mutations in dlg result in a poorly developed and much simpler SSR. Developmental studies show that in wild type, the surface of this postsynaptic structure increases (about 100-fold) as the target muscle becomes larger (over 100 times in volume) during larval growth (Guan, 1996). In the mutant, the SSR forms normally at initial larval stages, but fails to expand as target muscles grow. Postsynaptic DLG is able to substantially rescue the SSR phenotype. These results support the model that suggests that DLG is involved in adjusting the size of postsynaptic surfaces during development (Burdnik, 1996).

What is the presynaptic function of DLG? DLG is observed in the presynaptic cell prior to its expression in the postsynaptic cell (Guan, 1996). The expression of DLG in the presynaptic cell may target ion channels and other proteins to the presynaptic terminal and activate the release of an agrin-like molecule, which induces the synthesis of rapsyn-like synapse-orienting proteins, such as DLG in the postsynaptic cell. Mutation of dlg result in larger synaptic currents at fly neuromuscular junctions. The enlarged excitatory junctional current (EJC) amplitude in dlg mutants is caused by an increase in the number of vesicles released during each stimulus (quantal content). Rescue of the physiological defect is accomplished by presynaptic, but not postsynaptic targeted expression of dlg. Thus presynaptic dlg expression can rescue the neurotransmitter release phenotype. Additionally, and paradoxically, presynaptic dlg expression can rescue the postsynaptic SSR structure as well (Budnik, 1996).

Organizing a functional junctional complex requires specific domains of the Drosophila MAGUK discs large

Discs large (Dlg) was the first identified member of an increasingly important class of proteins called membrane-associated guanylate kinase homologs (MAGUKs), which are often concentrated at cell junctions and contain distinct peptide domains named PDZ1-3, SH3, HOOK, and GUK. The region between the Sh3 and GUK domains (HOOK, or I3) shows significant sequence similarity between several MAGUKs: in hDlg and p55, it has been shown to bind certain actin-associated proteins of the protein 4.1/ERM (Exrin, Radizin, Moesin) superfamily (Hough, 1997).

Dlg is localized at and required for the formation of both septate junctions in epithelial cells and synaptic junctions in neurons. In the absence of Dlg, epithelia lose their organization and overgrow. The functions of each domain of Dlg were tested in vivo by constructing transgenic flies expressing altered forms of the protein. In the first set of experiments each domain was examined for its ability to correctly target an epitope-tagged Dlg to pre-existing septate junctions. Based on these results the Hook domain is necessary for localization of the protein to the cell membrane and the PDZ2 domain is required for restricting the protein to the septate junction. In the second set of experiments, each domain was tested for its role in growth regulation and organization of epithelial structure. These results show that PDZ1 and GUK are apparently dispensable for function; PDZ2 and PDZ3 are required for growth regulation but not for epithelial structure, and SH3 and HOOK are essential for both aspects of function. The results demonstrate the functional modularity of Dlg and clarify the functions of individual MAGUK domains in regulating the structure and growth of epithelial tissue (Hough, 1997).

A three-step model is proposed for Dlg localization to the septate junctions and binding of the proteins important for structure and growth regulation. Step one involves binding of the HOOK domain to a protein 4.1-like protein and membrane localization of Dlg. Step two, mediating Dlg clustering at septate junctions, involves transmembrane protein binding to PDZ1/2 and Step three involves stabilization and binding of proteins involved in additional functions, such as growth regulation. The relative order of these steps is unknown. The effect of dlg mutations may not be an indirect consequence of loss of junctional structure, but may reflect a direct role of the Dlg protein in the signaling events that control proliferation (Hough, 1997).

DLGS97/SAP97 is developmentally upregulated and is required for complex adult behaviors and synapse morphology and function

The synaptic membrane-associated guanylate kinase (MAGUK) scaffolding protein family is thought to play key roles in synapse assembly and synaptic plasticity. Evidence supporting these roles in vivo is scarce, as a consequence of gene redundancy in mammals. The genome of Drosophila contains only one MAGUK gene, discs large (dlg), from which two major proteins originate: DLGA [PSD95 (postsynaptic density 95)-like] and DLGS97 [SAP97 (synapse-associated protein)-like]. These differ only by the inclusion in DLGS97 of an L27 domain, important for the formation of supramolecular assemblies. Known dlg mutations affect both forms and are lethal at larval stages attributable to tumoral overgrowth of epithelia. Independent null mutations were generated for each, dlgA and dlgS97. These allowed unveiling of a shift in expression during the development of the nervous system: predominant expression of DLGA in the embryo, balanced expression of both during larval stages, and almost exclusive DLGS97 expression in the adult brain. Loss of embryonic DLGS97 does not alter the development of the nervous system. At larval stages, DLGA and DLGS97 fulfill both unique and partially redundant functions in the neuromuscular junction. Contrary to dlg and dlgA mutants, dlgS97 mutants are viable to adulthood, but they exhibit marked alterations in complex behaviors such as phototaxis, circadian activity, and courtship, whereas simpler behaviors like locomotion and odor and light perception are spared. It is proposed that the increased repertoire of associations of a synaptic scaffold protein given by an additional domain of protein-protein interaction underlies its ability to integrate molecular networks required for complex functions in adult synapses (Mendoza-Topaz, 2008).

Although the in vivo function of the L27 domain of DLGS97/SAP97 in neurons is not fully understood, it has been implicated in AMPA receptor trafficking, in the synaptic localization of Dlin-7, in activity-dependent redistribution of AMPA receptors to spines, and in postsynaptic clustering. L27 domains are found in proteins of the MAGUK family and in proteins of the LIN-7 family and have been widely implicated in the homo-oligomerization and hetero-oligomerization of these scaffolding proteins. The L27 domain of DLGS97 could coordinate the function of many multiprotein complexes, consisting of a scaffolding protein and all its binding partners. In vertebrates, SAP97 associates through its L27 domain with the first L27 of CASK, which in turn associates through its second L27 to the L27 of LIN-7/MALS. The existence of a similar complex in flies is supported by the presence of CASK (CAKI) and LIN-7 (dLIN-7) homologues and the in vitro interaction between CAKI and the L27 of DLGS97. CAKI is expressed in a pattern similar to DLG in adults and caki mutants, like dlgS97 mutants, are viable. These mutants show locomotor speed defects and abnormal optomotor behavior, although no other behaviors have been examined. CAKI has also been suggested to be involved in the regulation of the autonomous activity of CaMKII regulating its activation and deactivation and shown to be important for the male habituation behavior during mating. In vertebrates, SAP97/CASK/VELI complex has been implicated in the transport of glutamate receptors as well as in the recruitment of SAP97 to the membrane. Thus, DLGS97 is likely to form supramolecular complexes, in which the specific function of lower order complexes is harmonized and perhaps synchronized. The observation that DLGS97 appears to play a role in behaviors that require multiple sensory and motor pathways makes the speculation that DLGS97 control the coordination of complexes involved in the regulation of CaMKII activity and/or the delivery of receptors at the synapse highly attractive (Mendoza-Topaz, 2008).

Another feature DLGS97 proteins have is their ability to regulate the switch-like characteristics of MAGUKs. The GUK and SH3 domains of PSD95 and SAP97 can establish intramolecular interactions rendering the proteins in an open (available for partner binding) or closed configuration. Notably, the N-terminal extension of SAP97 can inhibit these intramolecular interactions. Thus, L27 domain-containing proteins have an additional level of regulation able to regulate MAGUK interactions with binding partners (Mendoza-Topaz, 2008).

Remarkably, a recent report shows that the mammalian MAGUKs PSD95 and SAP97 are expressed in the CNS as alternative splice forms containing or lacking an L27 domain. Furthermore, these studies suggest that only the L27 domain-bearing forms are sensitive to activity associated to the CaMKII activity, supporting a role of the L27 domain in activity-induced synaptic modification (Mendoza-Topaz, 2008).

A significant finding in this work is the versatility of SAP proteins within the same cell. Although eliminating either of the two isoforms did not prevent normal localization of Scrib, FasII localization was altered in both dlgS97 and dlgA mutants, although the total amount of DLG was only decreased at most by 20%. These observations are intriguing, given that FasII and Scrib interact with DLG domains present in both isoforms. This suggests that form-specific characteristics or the interaction or balance between the two proteins are important for proper FasII localization. Similar codependence/independence between isoforms was found at the ultrastructural level. Although both isoforms appeared to be required for the regulation of active zones, bouton and synaptic vesicle size, either of them had functions in SSR development (Mendoza-Topaz, 2008).

The detected abnormalities in synaptic architecture were also accompanied by functional alterations. The mEJP amplitude change of dlgXI-2 was phenocopied when DLGS97 was eliminated, whereas the absence of DLGA did not increase the amplitude of the mEJPs. The increase of mEJPs amplitude was correlated with an increase in the size of the vesicles (significant for all genotypes) and an increase in the labeling intensity and size of the GluR clusters only in dlgS97 mutants. Thus, the increased mEJP amplitude in dlgS97 mutants correlates with presynaptic and postsynaptic defects. However, the decrease in EJP amplitude depended only on DLGA. Overall, both mutants had a decrease in quantal content, indicating that both isoforms are required for effective neurotransmission. Such SAP-specific functions between PSD95 and SAP97 have been suggested in neuronal culture studies (Mendoza-Topaz, 2008).

A striking shift was fund in isoform usage during development, with DLGS97 becoming increasingly preponderant at more mature stages. These results, added to the previously described DLGS97 exclusive expression in excitable tissues, suggest that this shift underscores a fundamental and unique requirement of the L27 domain in neurons. A similar developmental shift is observed in mammalian neuronal cultures, in which PSD95 and PSD93 (proteins that bear L27 domains as splice variants) play most relevant roles in mature neurons, whereas SAP102 (lacking L27 domain) is essential in immature neurons. Thus, although SAPs devoid of L27 domain might have roles in protein clustering in a broad number of polarized cells, L27-bearing SAPs might couple the basic clustering machinery to multiple cellular processes. Isolation of isoform-specific mutants in the absence of SAP redundancy constitutes the first step to address this possibility (Mendoza-Topaz, 2008).

This study highlights the correlation between the acquisition of a single domain of protein-protein interaction and the ability of DLGS97 to engage in processes required for complex functions of the adult brain. Although the mechanisms mediating between both levels need to be unraveled and are probably multiple, this example appears relevant to understand the elaboration of increasingly complex structures and functions with a limited set of molecular tools (Mendoza-Topaz, 2008).

The exon junction complex regulates the splicing of cell polarity gene dlg1 to control Wingless signaling in development

Wingless (Wg)/Wnt signaling is conserved in all metazoan animals and plays critical roles in development. The Wg/Wnt morphogen reception is essential for signal activation, whose activity is mediated through the receptor complex and a scaffold protein Dishevelled (Dsh). This study reports that the exon junction complex (EJC) activity is indispensable for Wg signaling by maintaining an appropriate level of Dsh protein for Wg ligand reception in Drosophila. Transcriptome analyses in Drosophila wing imaginal discs indicate that the EJC controls the splicing of the cell polarity gene discs large 1 (dlg1), whose coding protein directly interacts with Dsh. Genetic and biochemical experiments demonstrate that Dlg1 protein acts independently from its role in cell polarity to protect Dsh protein from lysosomal degradation. More importantly, human orthologous Dlg protein is sufficient to promote Dvl protein stabilization and Wnt signaling activity, thus revealing a conserved regulatory mechanism of Wg/Wnt signaling by Dlg and EJC (Liu, 2016).

The EJC is known to act in several aspects of posttranscriptional regulation, including mRNA localization, translation and degradation. After transcription, the pre-mRNA associated subunit eIF4AIII is loaded to nascent transcripts about 20-24 bases upstream of each exon junction, resulting in binding of Mago nashi (Mago)/Magoh and Tsunagi (Tsu)/Y14 proteins to form the pre-EJC core complex. The pre-EJC then recruits other proteins including Barentsz (Btz) to facilitate its diverse function). In vertebrates, the EJC is known to ensure translation efficiency as well as to activate nonsense-mediated mRNA decay (NMD). In Drosophila, however, the EJC does not contribute to NMD. It is instead required for the oskar mRNA localization to the posterior pole of the oocyte. Very recently, the pre-EJC has been shown to play an important role in alternative splicing of mRNA in Drosophila. Reduced EJC expression results in two forms of aberrant splicing. One is the exon skipping, which occurs in MAPK and transcripts that contain long introns or are located at heterochromatin (Ashton-Beaucage, 2010; Roignant, 2010). The other is the intron retention on piwi transcripts. Furthermore, transcriptome analyses in cultured cells indicates the role of EJC in alternative splicing is also conserved in vertebrates (Liu, 2016).

This study has utilized the developing Drosophila wing as an in vivo model system to investigate new mode of regulation of Wg signaling. The pre-EJC was found to positively regulate Wg signaling through its effect on facilitating Wg morphogen reception. Further studies reveal that the basolateral cell polarity gene discs large 1 (dlg1) is an in vivo target of the pre-EJC in Wg signaling. Dlg1 acts independently from its role on cell polarity to stabilize Dsh protein, thus allowing Wg protein internalization required for signaling activation. Furthermore, it was demonstrated that human Dlg2 exhibits a similar protective role on Dvl proteins to enhance Wnt signaling in cultured human cells. Taken together, this study unveils a conserved regulatory mechanism of the EJC and Dlg in Wg/Wnt signaling (Liu, 2016).

In summary, this study uncovers a specific role of the RNA binding protein complex EJC in the Drosophila wing morphogenesis. Genetic and biochemical analyses demonstrate that the pre-EJC is necessary for Wg morphogen reception to activate the signal transduction. The identification of the cell polarity determinant dlg1 as one of the pre-EJC targets provides mechanistic basis for the pre-EJC regulation of the Wg signaling. Dlg1 controls the stability of the scaffold protein Dsh, which is the hub of the Wg signaling cascade. Importantly, this mode of regulation of Dvl by Dlg is conserved from flies to vertebrates (Liu, 2016).

The EJC as well as other RNA binding protein complexes are thought to function in a pleiotropic manner. However, the current data together with several recent studies argue that RNA regulatory machineries can act specifically on developmental signaling for pattern formation and organogenesis. It has been increasingly recognized that the production, transport or the location of mRNA are subject to precise regulation in Wg/Wnt signaling. For example, apical localization of wg RNA is essential for signal activation in epithelial cells. The specific role of RNA machineries on cell signaling is not limited to Wg/Wnt signaling. It has been reported that RNA-binding protein Quaking specifically binds to the 3'UTR of transcription factor gli2a mRNA to modulate Hedgehog signaling in zebrafish muscle development. RNA binding protein RBM5/6 and 10 could differentially control alternative splicing of a negative Notch regulator gene NUMB, thus antagonistically regulating the Notch signaling activity for cancer cell proliferation. Therefore, generally believed pleotropic RNA regulatory machineries emerge as important regulatory means to specifically control cell signaling and related developmental processes (Liu, 2016).

The most studied function of the EJC in development is to localize oskar mRNA to the posterior pole of the oocyte for oocyte polarity establishment and germ cell formation in Drosophila. Further study suggests that the proper oskar RNA localization relies on its mRNA splicing. In light of the current study of the EJC activity on dlg1 mRNA as well as the roles of EJC on mapk and piwi splicing, it is suspected that EJC might regulate oskar mRNA splicing to mediate its mRNA localization. RNA-seq analyses identified several hundreds of candidate mRNAs whose expression may be directly or indirectly subjected to EJC regulation. Apart from defects in Wg and MAPK signaling, however, altered wing patterning associated with other developmental signaling systems was not seen in EJC defective flies, arguing that EJC may primarily regulate Wg and MAPK signaling in patterning the developing wing (Liu, 2016).

Wg/Wnt signaling plays a fundamental role in development and tissue homeostasis in both flies and vertebrates. Its activation and maintenance rely on appropriate activity of the ternary receptor complex including Fz family proteins. In Drosophila, polarized localization of Fz and Fz2 proteins is essential for activation of non-canonical and canonical Wg signaling, respectively. Dsh, which acts as a hub mediating both canonical and non-canonical Wg signaling, however, is found at both the apical cell boundary and in the basal side of the cytoplasm. Thus, the polarized activity of Dsh must require distinct regulatory mechanisms at different sub-membrane compartments. The results provide the in vivo evidence suggesting that the basolateral polarity determinant Dlg1 may play a dominant role to control the Dsh abundance/activity in canonical Wg signaling (Liu, 2016).

Altered Dvl production or activity has been linked with several forms of cancer. The stability of Dvl proteins can be controlled through regulated protein degradation both in vertebrates and in Drosophila as reported in this study. In HEK293T cells, Dapper1 induces whilst Myc-interacting zinc-finger protein 1 (MIZ1) antagonizes autophagic degradation of Dvl2 in lysosome. It is also reported that a tumor suppressor CYLD deubiquitinase inhibits the ubiquitination of Dvl. As Dlg1 prevents Dsh from degradation in Drosophila, it is important to investigate if Dlg1 participates in a posttranslational regulatory network of Dvl to integrate endocytosis and autophagy. Furthermore, upregulation of dvl2 and dlg2 expression has been found in various forms of cancer as shown in the COSMIC database. The study of the interaction between Dlg1 and Dsh may aid the development of novel approaches to prevent or treat relevant diseases. (Liu, 2016).

Dlg1 acts together with L(2)gl to form a basolateral complex in polarized epithelium. Dsh is known to interact with L(2)gl. On one hand, Dsh activity is required for correct localization of L(2)gl to establish apical-basal polarity in Xenopus ectoderm and Drosophila follicular epithelium. On the other hand, L(2)gl can regulate Dsh to maintain planar organization of the embryonic epidermis in Drosophila. Despite the complex interaction between L(2)gl and Dsh, not much is known about mutual regulation between Dlg1 and Dsh. A recent report suggests that Dsh binds to Dlg1 to activate Guk Holder-dependent spindle positioning in Drosophila. The current results unveil another side of the relationship in which Dlg1 controls the turnover of Dsh to ensure developmental signal propagation. Apart from its apical localization at the cell boundary, Dsh is also found in the basal side of the cytoplasm. It is likely that the interactions among Dsh, Dlg1 and L(2)gl may be dependent on their localization, and Dsh may serve as a bridge to connect cell signaling and polarity (Liu, 2016).

Developmental signaling and cell polarity intertwine to control a diverse array of cellular events. It is well known that Wg/Wnt signaling controls cell polarity in distinct manner. Non-canonical signaling acts through cytoskeletal regulators to establish planar cell polarity. Canonical signaling may also directly affect apical-basal cell polarity. On the other hand, disruption of epithelial cell polarity has a profound impact on protein endocytosis and recycling, both of which are essential regulatory steps for signal activation and maintenance. The current results add another layer of complexity by which polarity determinants could contribute to cell signaling independent of their conventional roles in polarity establishment and maintenance. Interestingly, this mode of regulation is also observed for other signaling processes. Loss of Dlg5 impairs Sonic hedgehog-induced Gli2 accumulation at the ciliary tip in mouse fibroblast cells that may not rely on cell polarity regulation. Similarly, L(2)gl regulates Notch signaling via endocytosis, independent of its role in cell polarity. It is believed that other cell polarity determinants may similarly participate in polarity-independent processes, however, the exact mechanism of how they cooperate to modulate developmental signaling awaits further investigation (Liu, 2016).


PROTEIN STRUCTURE

Amino Acids - 959

Structural Domains

DLG contains a domain homologous to yeast guanylate kinase and a region homologous to SH3, a putative regulatory motif in nonreceptor protein tyrosine kinases and other signal transduction proteins (Woods, 1989 and 1991).

The ExPASy World Wide Web (WWW) molecular biology server of the Geneva University Hospital and the University of Geneva provides extensive documentation for the Guanylate kinase pattern.


discs large 1: Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

date revised: 21 APR 97 

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