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      Modeling of the Dorsal Gradient across Species Reveals Interaction between Embryo Morphology and Toll Signaling Pathway during Evolution

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          Abstract

          Morphogenetic gradients are essential to allocate cell fates in embryos of varying sizes within and across closely related species. We previously showed that the maternal NF-κB/Dorsal (Dl) gradient has acquired different shapes in Drosophila species, which result in unequally scaled germ layers along the dorso-ventral axis and the repositioning of the neuroectodermal borders. Here we combined experimentation and mathematical modeling to investigate which factors might have contributed to the fast evolutionary changes of this gradient. To this end, we modified a previously developed model that employs differential equations of the main biochemical interactions of the Toll (Tl) signaling pathway, which regulates Dl nuclear transport. The original model simulations fit well the D. melanogaster wild type, but not mutant conditions. To broaden the applicability of this model and probe evolutionary changes in gradient distributions, we adjusted a set of 19 independent parameters to reproduce three quantified experimental conditions (i.e. Dl levels lowered, nuclear size and density increased or decreased). We next searched for the most relevant parameters that reproduce the species-specific Dl gradients. We show that adjusting parameters relative to morphological traits (i.e. embryo diameter, nuclear size and density) alone is not sufficient to reproduce the species Dl gradients. Since components of the Tl pathway simulated by the model are fast-evolving, we next asked which parameters related to Tl would most effectively reproduce these gradients and identified a particular subset. A sensitivity analysis reveals the existence of nonlinear interactions between the two fast-evolving traits tested above, namely the embryonic morphological changes and Tl pathway components. Our modeling further suggests that distinct Dl gradient shapes observed in closely related melanogaster sub-group lineages may be caused by similar sequence modifications in Tl pathway components, which are in agreement with their phylogenetic relationships.

          Author Summary

          Embryo size can vary greatly among closely related species. How tissue specification either scales or is modified in the developing embryo in different species is an ongoing investigation in developmental biology. Here we asked how embryo morphology and specific molecular pathways influence tissue specification by altering the distribution of morphogens. Morphogens are molecules that form gradients that regulate gene expression patterns in a dosage-dependent fashion that result in tissue specification, and therefore are a prime target for evolution in order to adjust or maintain tissue proportions in relation to overall embryo size. We used a mathematical model to identify factors that influence the distribution of the Dorsal morphogen gradient that is responsible for patterning the dorsal-ventral axis of the Drosophila fruit fly embryo. We obtained experimental data from mutant conditions and different species of Drosophila to calibrate our model and found an interaction between embryo morphology and regulation of the Toll pathway, which regulates the Dorsal gradient. Furthermore, the model predicts that closely related species share similar modifications in Toll pathway components resulting in their species-specific gradient shapes, which are supported by interspecies amino acid comparison of the components Dorsal and Cactus.

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          Most cited references38

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          Evolution of genes and genomes on the Drosophila phylogeny.

          Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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            Morphogen gradients: from generation to interpretation.

            Morphogens are long-range signaling molecules that pattern developing tissues in a concentration-dependent manner. The graded activity of morphogens within tissues exposes cells to different signal levels and leads to region-specific transcriptional responses and cell fates. In its simplest incarnation, a morphogen signal forms a gradient by diffusion from a local source and clearance in surrounding tissues. Responding cells often transduce morphogen levels in a linear fashion, which results in the graded activation of transcriptional effectors. The concentration-dependent expression of morphogen target genes is achieved by their different binding affinities for transcriptional effectors as well as inputs from other transcriptional regulators. Morphogen distribution and interpretation are the result of complex interactions between the morphogen and responding tissues. The response to a morphogen is dependent not simply on morphogen concentration but also on the duration of morphogen exposure and the state of the target cells. In this review, we describe the morphogen concept and discuss the mechanisms that underlie the generation, modulation, and interpretation of morphogen gradients.
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              Stability and nuclear dynamics of the bicoid morphogen gradient.

              Patterning in multicellular organisms results from spatial gradients in morphogen concentration, but the dynamics of these gradients remain largely unexplored. We characterize, through in vivo optical imaging, the development and stability of the Bicoid morphogen gradient in Drosophila embryos that express a Bicoid-eGFP fusion protein. The gradient is established rapidly (approximately 1 hr after fertilization), with nuclear Bicoid concentration rising and falling during mitosis. Interphase levels result from a rapid equilibrium between Bicoid uptake and removal. Initial interphase concentration in nuclei in successive cycles is constant (+/-10%), demonstrating a form of gradient stability, but it subsequently decays by approximately 30%. Both direct photobleaching measurements and indirect estimates of Bicoid-eGFP diffusion constants (D < or = 1 microm(2)/s) provide a consistent picture of Bicoid transport on short ( approximately min) time scales but challenge traditional models of long-range gradient formation. A new model is presented emphasizing the possible role of nuclear dynamics in shaping and scaling the gradient.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Comput Biol
                PLoS Comput. Biol
                plos
                ploscomp
                PLoS Computational Biology
                Public Library of Science (San Francisco, USA )
                1553-734X
                1553-7358
                August 2014
                28 August 2014
                : 10
                : 8
                : e1003807
                Affiliations
                [1 ]Department of Biology, Case Western Reserve University, Cleveland, Ohio, United States of America
                [2 ]Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America
                North Carolina State University, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: PA JSC HJC CMM. Performed the experiments: PA HRK JSC CMM. Analyzed the data: PA HRK JSC HJC CMM. Contributed to the writing of the manuscript: PA JSC CMM.

                [¤]

                Current address: Department of Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

                Article
                PCOMPBIOL-D-14-00822
                10.1371/journal.pcbi.1003807
                4148200
                25165818
                caf31589-6ba7-4ba7-a001-a19aeed862f5
                Copyright @ 2014

                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
                : 12 May 2014
                : 14 July 2014
                Page count
                Pages: 17
                Funding
                This work was funded by a National Science Foundation grant number IOS-1051662 to CMM; a National Institutes of Health grant number 1R21EB016535-01 to CMM and Case Western Reserve University startup funds to CMM. PA was supported by a CAPES/Brasilia fellowship under the Brazil Science without Borders program. JSC was supported by the College of Arts and Sciences/CWRU. HRK was supported by a HHMI grant number 52005866 for support of undergraduate education in the biological sciences. 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
                Developmental Biology
                Molecular Development
                Morphogens
                Cell Fate Determination
                Evolutionary Developmental Biology
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

                Quantitative & Systems biology
                Quantitative & Systems biology

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