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

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.Peer reviewe

Scribble and alpha-Catenin cooperatively regulate epithelial homeostasis and growth

Epithelial homeostasis is an emergent property of both physical and biochemical signals emanating from neighboring cells and across tissue. A recent study reveals that Scribble, an apico-basal polarity determinant, cooperates with alpha-Catenin, an adherens junction component, to regulate tissue homeostasis in the Drosophila wing imaginal disc. However, it remains to be addressed whether similar mechanisms are utilized in vertebrates. In this study, we first address how alpha-Catenin cooperates with Scribble to regulate epithelial homeostasis and growth in mammalian cells. Our data show that alpha-Catenin and Scribble interact physically in mammalian cells. We then found that both alpha-Catenin and Scribble are required for regulating nuclear translocation of YAP, an effector of the Hippo signaling pathway. Furthermore, ectopic Scribble suffices to suppress YAP in an alpha-Catenin-dependent manner. Then, to test our hypothesis that Scribble amounts impact epithelial growth, we use the Drosophila wing imaginal disc. We show that Scribble expression is complementary to Yorkie signal, the Drosophila ortholog of YAP. Ectopic expression of full-length Scribble or Scribble Leucine Rich Region (LRR):alpha-Catenin chimera sufficiently down-regulates Yorkie signal, leading to smaller wing size. Moreover, Scribble LRR:alpha-Catenin chimera rescues scribble mutant clones in the wing imaginal disc to maintain tissue homeostasis. Taken together, our studies suggest that the association of cell polarity component Scribble with alpha-Catenin plays a conserved role in epithelial homeostasis and growth.Peer reviewe

Coupling between dynamic 3D tissue architecture and BMP morphogen signaling during Drosophila wing morphogenesis

At the level of organ formation, tissue morphogenesis drives developmental processes in animals, often involving the rearrangement of two-dimensional (2D) structures into more complex three-dimensional (3D) tissues. These processes can be directed by growth factor signaling pathways. However, little is known about how such morphological changes affect the spatiotemporal distribution of growth factor signaling. Here, using the Drosophila pupal wing, we address how decapentaplegic (Dpp)/bone morphogenetic protein (BMP) signaling and 3D wing morphogenesis are coordinated. Dpp, expressed in the longitudinal veins (LVs) of the pupal wing, initially diffuses laterally within both dorsal and ventral wing epithelia during the inflation stage to regulate cell proliferation. Dpp localization is then refined to the LVs within each epithelial plane, but with active interplanar signaling for vein patterning/differentiation, as the two epithelia appose. Our data further suggest that the 3D architecture of the wing epithelia and the spatial distribution of BMP signaling are tightly coupled, revealing that 3D morphogenesis is an emergent property of the interactions between extracellular signaling and tissue shape changes.Peer reviewe

Heterogeneous temporal representation for diabetic blood glucose prediction

Background and aims: Blood glucose prediction (BGP) has increasingly been adopted for personalized monitoring of blood glucose levels in diabetic patients, providing valuable support for physicians in diagnosis and treatment planning. Despite the remarkable success achieved, applying BGP in multi-patient scenarios remains problematic, largely due to the inherent heterogeneity and uncertain nature of continuous glucose monitoring (CGM) data obtained from diverse patient profiles.Methodology: This study proposes the first graph-based Heterogeneous Temporal Representation (HETER) network for multi-patient Blood Glucose Prediction (BGP). Specifically, HETER employs a flexible subsequence repetition method (SSR) to align the heterogeneous input samples, in contrast to the traditional padding or truncation methods. Then, the relationships between multiple samples are constructed as a graph and learned by HETER to capture global temporal characteristics. Moreover, to address the limitations of conventional graph neural networks in capturing local temporal dependencies and providing linear representations, HETER incorporates both a temporally-enhanced mechanism and a linear residual fusion into its architecture.Results: Comprehensive experiments were conducted to validate the proposed method using real-world data from 112 patients in two hospitals, comparing it with five well-known baseline methods. The experimental results verify the robustness and accuracy of the proposed HETER, which achieves the maximal improvement of 31.42%, 27.18%, and 34.85% in terms of MAE, MAPE, and RMSE, respectively, over the second-best comparable method.Discussions: HETER integrates global and local temporal information from multi-patient samples to alleviate the impact of heterogeneity and uncertainty. This method can also be extended to other clinical tasks, thereby facilitating efficient and accurate capture of crucial pattern information in structured medical data

Regulation of Cell Polarity Determinant Scribble in Drosophila and Mammals

Epithelial morphogenesis is one of the crucial processes of tissue development, and is mediated by cell-cell communication. A key characteristic of epithelial cells is their polarization along the apical-basal axis. Loss of cell polarity often leads to neoplasia in metazoans, therefore several key components involved in apicobasal polarity formation have been identified to be tumour suppressors. However, it remains largely unknown how epithelial polarity and growth control are mutually coordinated. By using Drosophila melanogaster wing development and mammalian cell culture as model systems, this study aims to address mechanisms underlying apicobasal polarity and tissue development. In the Drosophila wing imaginal disc, via studying polarity determinant Scribble (Scrib), this study reveals that cell polarity is regulated through intercellular mechanism. Conditional knockdown of scrib in a stripe of cells in the wing imaginal disc results in loss of polarity in adjacent wild type cells, ultimately leading to neoplasia. Yorkie activity, an effector of the Hippo signalling pathway, is required for the expansion of loss of cell polarity. The data show that genetic interaction between the septate junction (SJ), Scribble and α-Catenin axis plays an important role in intercellular regulation of cell polarity. Next, this study demonstrates that Scribble physically interacts with α-catenin (α-Cat), and this interaction is conserved in Drosophila and mammals. The Scrib-α-Cat association helps stabilize localization of Scribble and regulates tissue homeostasis in Drosophila. The complex of Scrib and α-Cat regulates cell proliferation through the Hippo pathway in Drosophila and mammalian cells. In Drosophila, BMP/Dpp signalling is crucial for wing vein morphogenesis. In pupal wing, Dpp is expressed in the longitudinal veins (LVs) and is transported to the posterior crossvein (PCV) region to induce PCV morphogenesis. This study reveals that Scribble is required for PCV development. The data show that Scribble regulates BMP signalling by affecting the internalization of BMP type I receptor Thickveins (Tkv) in the PCV region. BMP signalling induces Scribble transcription, thus forming a feedback loop between Scrib and BMP signalling, which play a crucial role in PCV morphogenesis. Overall, this study reveals that Scribble plays a unique role in tissue growth in a non-autonomous manner through regulating apicobasal polarity at the tissue level. Conserved roles of interaction between Scribble and α-Cat in vertebrates and invertebrates provide important insights into tissue growth and homeostasis. Finally, Scribble contributes to pattern formation by forming a feedback loop with BMP signalling in tissue development. Taken together, this thesis work provides novel insights into how polarity determinant Scribble is utilized for tissue development through its interactions with multiple partners.Tiivistelmä ei saatavilla

Wing vein development in the sawfly Athalia rosae is regulated by spatial transcription of Dpp/BMP signaling components

Wing venation among insects serves as an excellent model to address how diversified patterns are produced. Previous studies suggest that evolutionarily conserved Decapentaplegic (Dpp)/Bone Morphogenetic Protein (BMP) signal plays a critical role in wing vein development in the dipteran Drosophila melanogaster and the hymenopteran sawfly Athalia rosae. In sawfly, dpp is ubiquitously expressed in the wing during prepupal stages, but Dpp/BMP signal is localized in the future vein cells. Since localized BMP signaling involves BMP binding protein Crossveinless (Cv), redistribution of BMP ligands appears to be crucial for sawfly wing vein formation. However, how ubiquitously expressed ligands lead to a localized signal remains to be addressed. Here, we found that BMP binding protein short gastrulation (Sog) is highly expressed in the intervein cells. Our data also reveal that BMP type I receptors thickveins (Tkv) and saxophone (Sax) are highly expressed in intervein cells and at lower levels in the vein progenitor cells. RNAi knockdown of Ar-tkv or Ar-sax indicates that both receptors are required for localized BMP signaling in the wing vein progenitor cells. Taken together, our data suggest that spatial transcription of core- and co-factors of the BMP pathway sustain localized BMP signaling during sawfly wing vein development. (C) 2018 Elsevier Ltd. All rights reserved.Peer reviewe

Quantitative Morphological Variation in the Developing Drosophila Wing

Quantitative genetic variation in morphology is pervasive in all species and is the basis for the evolution of differences among species. The measurement of morphological form in adults is now beginning to be combined with comparable measurements of form during development. Here we compare the shape of the developing wing to its adult form in a holometabolous insect, Drosophila melanogaster. We used protein expression patterns to measure shape in the developing precursors of the final adult wing. Three developmental stages were studied: late larval third instar, post-pupariation and in the adult fly. We studied wild-type animals in addition to mutants of two genes (shf and ds) that have known effects on adult wing shape and size. Despite experimental noise related to the difficulty of comparing developing structures, we found consistent differences in wing shape and size at each developmental stage between genotypes. Quantitative comparisons of variation arising at different developmental stages with the variation in the final structure enable us to determine when variation arises, and to generate hypotheses about the causes of that variation. In addition we provide linear rules allowing us to link wing morphology in the larva, with wing morphology in the pupa. Our approach provides a framework to analyze quantitative morphological variation in the developing fly wing. This framework should help to characterize the natural variation of the larval and pupal wing shape, and to measure the contribution of the processes occurring during these developmental stages to the natural variation in adult wing morphology.Peer reviewe