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      Scribbled Optimizes BMP Signaling through Its Receptor Internalization to the Rab5 Endosome and Promote Robust Epithelial Morphogenesis

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      PLoS Genetics
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          Abstract

          Epithelial cells are characterized by apical-basal polarity. Intrinsic factors underlying apical-basal polarity are crucial for tissue homeostasis and have often been identified to be tumor suppressors. Patterning and differentiation of epithelia are key processes of epithelial morphogenesis and are frequently regulated by highly conserved extrinsic factors. However, due to the complexity of morphogenesis, the mechanisms of precise interpretation of signal transduction as well as spatiotemporal control of extrinsic cues during dynamic morphogenesis remain poorly understood. Wing posterior crossvein (PCV) formation in Drosophila serves as a unique model to address how epithelial morphogenesis is regulated by secreted growth factors. Decapentaplegic (Dpp), a conserved bone morphogenetic protein (BMP)-type ligand, is directionally trafficked from longitudinal veins (LVs) into the PCV region for patterning and differentiation. Our data reveal that the basolateral determinant Scribbled (Scrib) is required for PCV formation through optimizing BMP signaling. Scrib regulates BMP-type I receptor Thickveins (Tkv) localization at the basolateral region of PCV cells and subsequently facilitates Tkv internalization to Rab5 endosomes, where Tkv is active. BMP signaling also up-regulates scrib transcription in the pupal wing to form a positive feedback loop. Our data reveal a unique mechanism in which intrinsic polarity genes and extrinsic cues are coupled to promote robust morphogenesis.

          Author Summary

          Epithelial morphogenesis is one of the key processes in animal development. Evolutionarily conserved growth factors frequently instruct patterning and differentiation in morphogenesis. However, little is known about how extracellular cues and epithelial morphogenesis are mutually coordinated in vivo. Wing posterior crossvein (PCV) development in Drosophila provides an excellent system for understanding how bone morphogenetic protein (BMP) signaling regulates patterning and differentiation of epithelia. We find that the apical-basal polarity gene Scribbled (Scrib) is required for PCV formation by optimizing BMP signaling in the PCV region as follows. First, Scrib regulates BMP type-I receptor Thickveins (Tkv) localization basally. Second, Scrib facilitates Tkv internalization to the Rab5 endosomes to optimize signal transduction after receptor-ligand binding. Third, BMP signaling up-regulates scrib transcription in the pupal wing to form a positive feedback loop. These results suggest that coupling between epithelial polarity genes and conserved growth factors play crucial roles in patterning and differentiation of epithelia.

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          Most cited references40

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          An optimized transgenesis system for Drosophila using germ-line-specific phiC31 integrases.

          Germ-line transformation via transposable elements is a powerful tool to study gene function in Drosophila melanogaster. However, some inherent characteristics of transposon-mediated transgenesis limit its use for transgene analysis. Here, we circumvent these limitations by optimizing a phiC31-based integration system. We generated a collection of lines with precisely mapped attP sites that allow the insertion of transgenes into many different predetermined intergenic locations throughout the fly genome. By using regulatory elements of the nanos and vasa genes, we established endogenous sources of the phiC31 integrase, eliminating the difficulties of coinjecting integrase mRNA and raising the transformation efficiency. Moreover, to discriminate between specific and rare nonspecific integration events, a white gene-based reconstitution system was generated that enables visual selection for precise attP targeting. Finally, we demonstrate that our chromosomal attP sites can be modified in situ, extending their scope while retaining their properties as landing sites. The efficiency, ease-of-use, and versatility obtained here with the phiC31-based integration system represents an important advance in transgenesis and opens up the possibility of systematic, high-throughput screening of large cDNA sets and regulatory elements.
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            A protein trap strategy to detect GFP-tagged proteins expressed from their endogenous loci in Drosophila.

            In Drosophila, enhancer trap strategies allow rapid access to expression patterns, molecular data, and mutations in trapped genes. However, they do not give any information at the protein level, e.g., about the protein subcellular localization. Using the green fluorescent protein (GFP) as a mobile artificial exon carried by a transposable P-element, we have developed a protein trap system. We screened for individual flies, in which GFP tags full-length endogenous proteins expressed from their endogenous locus, allowing us to observe their cellular and subcellular distribution. GFP fusions are targeted to virtually any compartment of the cell. In the case of insertions in previously known genes, we observe that the subcellular localization of the fusion protein corresponds to the described distribution of the endogenous protein. The artificial GFP exon does not disturb upstream and downstream splicing events. Many insertions correspond to genes not predicted by the Drosophila Genome Project. Our results show the feasibility of a protein trap in Drosophila. GFP reveals in real time the dynamics of protein's distribution in the whole, live organism and provides useful markers for a number of cellular structures and compartments.
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              Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors.

              Loss of cell polarity and tissue architecture are characteristics of malignant cancers derived from epithelial tissues. We provide evidence from Drosophila that a group of membrane-associated proteins act in concert to regulate both epithelial structure and cell proliferation. Scribble (Scrib) is a cell junction-localized protein required for polarization of embryonic and, as demonstrated here, imaginal disc and follicular epithelia. We show that the tumor suppressors lethal giant larvae (lgl) and discs-large (dlg) have identical effects on all three epithelia, and that scrib also acts as a tumor suppressor. Scrib and Dlg colocalize and overlap with Lgl in epithelia; activity of all three genes is required for cortical localization of Lgl and junctional localization of Scrib and Dlg. scrib, dlg, and lgl show strong genetic interactions. Our data indicate that the three tumor suppressors act together in a common pathway to regulate cell polarity and growth control.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                4 November 2016
                November 2016
                : 12
                : 11
                : e1006424
                Affiliations
                [001]Institute of Biotechnology, University of Helsinki, Helsinki, Finland
                Harvard Medical School, Howard Hughes Medical Institute, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                • Conceptualization: JG OS.

                • Formal analysis: JG.

                • Funding acquisition: OS.

                • Investigation: JG YH.

                • Methodology: JG.

                • Supervision: OS.

                • Validation: JG OS.

                • Writing – original draft: JG OS.

                • Writing – review & editing: JG OS.

                Author information
                http://orcid.org/0000-0002-6442-4406
                http://orcid.org/0000-0001-6341-9130
                Article
                PGENETICS-D-16-00873
                10.1371/journal.pgen.1006424
                5096713
                27814354
                136e0379-a66d-4056-9bd0-5d2ab60c6159
                © 2016 Gui et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 18 April 2016
                : 12 October 2016
                Page count
                Figures: 6, Tables: 0, Pages: 19
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100005876, Biotieteiden ja Ympäristön Tutkimuksen Toimikunta;
                Award ID: 265648
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100006306, Sigrid Juséliuksen Säätiö;
                Award Recipient :
                Funded by: Integrative Life Science Doctoral Program
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100005876, Biotieteiden ja Ympäristön Tutkimuksen Toimikunta;
                Award ID: 272280
                Award Recipient :
                This work was supported by grant 265648 from the Academy of Finland, the Sigrid Juselius Foundation and Center of Excellence in Experimental and Computational Developmental Biology from the Academy of Finland to OS, and the Integrative Life Science Doctoral Program of the University of Helsinki to JG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and life sciences
                Cell biology
                Signal transduction
                Cell signaling
                BMP signaling
                Biology and life sciences
                Genetics
                Epigenetics
                RNA interference
                Biology and life sciences
                Genetics
                Gene expression
                RNA interference
                Biology and life sciences
                Genetics
                Genetic interference
                RNA interference
                Biology and life sciences
                Biochemistry
                Nucleic acids
                RNA
                RNA interference
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Cloning
                Research and Analysis Methods
                Molecular Biology Techniques
                Cloning
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Vesicles
                Endosomes
                Biology and Life Sciences
                Developmental Biology
                Morphogenesis
                Biology and Life Sciences
                Cell Biology
                Cell Physiology
                Cell Polarity
                Research and Analysis Methods
                Model Organisms
                Animal Models
                Drosophila Melanogaster
                Biology and Life Sciences
                Organisms
                Animals
                Invertebrates
                Arthropoda
                Insects
                Drosophila
                Drosophila Melanogaster
                Research and Analysis Methods
                Precipitation Techniques
                Immunoprecipitation
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Genetics
                Genetics

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