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A Feed-Forward Loop Coupling Extracellular BMP Transport and Morphogenesis in Drosophila Wing

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PLoS Genetics

Public Library of Science

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      Abstract

      A variety of extracellular factors regulate morphogenesis during development. However, coordination between extracellular signaling and dynamic morphogenesis is largely unexplored. We address the fundamental question by studying posterior crossvein (PCV) development in Drosophila as a model, in which long-range BMP transport from the longitudinal veins plays a critical role during the pupal stages. Here, we show that RhoGAP Crossveinless-C (Cv-C) is induced at the PCV primordial cells by BMP signaling and mediates PCV morphogenesis cell-autonomously by inactivating members of the Rho-type small GTPases. Intriguingly, we find that Cv-C is also required non-cell-autonomously for BMP transport into the PCV region, while a long-range BMP transport is guided toward ectopic wing vein regions by loss of the Rho-type small GTPases. We present evidence that low level of ß-integrin accumulation at the basal side of PCV epithelial cells regulated by Cv-C provides an optimal extracellular environment for guiding BMP transport. These data suggest that BMP transport and PCV morphogenesis are tightly coupled. Our study reveals a feed-forward mechanism that coordinates the spatial distribution of extracellular instructive cues and morphogenesis. The coupling mechanism may be widely utilized to achieve precise morphogenesis during development and homeostasis.

      Author Summary

      It has been extensively studied how tissue morphogenesis is regulated by a variety of extracellular cues. Given that dynamic morphogenesis coincides with arrival of extracellular factors, there must be also mechanisms that coordinate extracellular signaling and intracellular morphogenesis. However, the coordination is largely unknown, due to the complexity of morphogenesis in vivo. We addressed the fundamental question by studying posterior crossvein (PCV) development in Drosophila as a model, in which a long-range transport of bone morphogenetic protein (BMP) type ligands from adjacent longitudinal veins plays a critical role during the pupal stages. Here, we first showed that RhoGAP Crossveinless-C (Cv-C) is induced at the PCV region by BMP signal and mediates PCV morphogenesis. By modulating wing vein morphogenesis, we then found that PCV morphogenesis is required for BMP transport, while ectopic wing vein morphogenesis sufficiently guides a long-range BMP transport. These data suggest a feed-forward mechanism that coordinates the spatial distribution of extracellular instructive cues and morphogenesis. The coupling mechanism may be widely utilized to achieve precise tissue morphogenesis and tissue homeostasis.

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      The transforming growth factor beta (TGFbeta) signaling pathway is a key player in metazoan biology, and its misregulation can result in tumor development. The regulatory cytokine TGFbeta exerts tumor-suppressive effects that cancer cells must elude for malignant evolution. Yet, paradoxically, TGFbeta also modulates processes such as cell invasion, immune regulation, and microenvironment modification that cancer cells may exploit to their advantage. Consequently, the output of a TGFbeta response is highly contextual throughout development, across different tissues, and also in cancer. The mechanistic basis and clinical relevance of TGFbeta's role in cancer is becoming increasingly clear, paving the way for a better understanding of the complexity and therapeutic potential of this pathway.
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        Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis.

        We describe a genetic mosaic system in Drosophila, in which a dominant repressor of a cell marker is placed in trans to a mutant gene of interest. Mitotic recombination events between homologous chromosomes generate homozygous mutant cells, which are exclusively labeled due to loss of the repressor. Using this system, we are able to visualize axonal projections and dendritic elaboration in large neuroblast clones and single neuron clones with a membrane-targeted GFP marker. This new method allows for the study of gene functions in neuroblast proliferation, axon guidance, and dendritic elaboration in the complex central nervous system. As an example, we show that the short stop gene is required in mushroom body neurons for the extension and guidance of their axons.
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          Rho GTPases: biochemistry and biology.

          Approximately one percent of the human genome encodes proteins that either regulate or are regulated by direct interaction with members of the Rho family of small GTPases. Through a series of complex biochemical networks, these highly conserved molecular switches control some of the most fundamental processes of cell biology common to all eukaryotes, including morphogenesis, polarity, movement, and cell division. In the first part of this review, we present the best characterized of these biochemical pathways; in the second part, we attempt to integrate these molecular details into a biological context.
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            Author and article information

            Affiliations
            Institute of Biotechnology, University of Helsinki, Helsinki, Finland
            University of Pennsylvania School of Medicine, United States of America
            Author notes

            The authors have declared that no competing interests exist.

            Conceived and designed the experiments: SM OS. Performed the experiments: SM JB. Analyzed the data: SM. Contributed reagents/materials/analysis tools: SM JB. Wrote the paper: SM OS.

            Contributors
            Role: Editor
            Journal
            PLoS Genet
            PLoS Genet
            plos
            plosgen
            PLoS Genetics
            Public Library of Science (San Francisco, USA )
            1553-7390
            1553-7404
            March 2013
            March 2013
            21 March 2013
            : 9
            : 3
            23555308
            3605110
            PGENETICS-D-12-01963
            10.1371/journal.pgen.1003403
            (Editor)

            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.

            Counts
            Pages: 11
            Funding
            This work was supported by the University of Helsinki ( www.helsinki.fi/university) and the Sigrid Juselius Foundation ( www.sigridjuselius.fi). SM is supported by the Viikki Graduate School in Biosciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Biology
            Developmental Biology
            Molecular Development
            Adhesion Molecules
            Morphogens
            Signaling
            Organism Development
            Pattern Formation
            Cell Differentiation
            Cell Fate Determination
            Morphogenesis
            Pattern Formation
            Model Organisms
            Animal Models
            Drosophila Melanogaster

            Genetics

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