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      Lrp4/Wise regulates palatal rugae development through Turing-type reaction-diffusion mechanisms

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          Abstract

          Periodic patterning of iterative structures is diverse across the animal kingdom. Clarifying the molecular mechanisms involved in the formation of these structure helps to elucidate the process of organogenesis. Turing-type reaction-diffusion mechanisms have been shown to play a critical role in regulating periodic patterning in organogenesis. Palatal rugae are periodically patterned ridges situated on the hard palate of mammals. We have previously shown that the palatal rugae develop by a Turing-type reaction-diffusion mechanism, which is reliant upon Shh (as an inhibitor) and Fgf (as an activator) signaling for appropriate organization of these structures. The disturbance of Shh and Fgf signaling lead to disorganized palatal rugae. However, the mechanism itself is not fully understood. Here we found that Lrp4 (transmembrane protein) was expressed in a complementary pattern to Wise (a secreted BMP antagonist and Wnt modulator) expression in palatal rugae development, representing Lrp4 expression in developing rugae and Wise in the inter-rugal epithelium. Highly disorganized palatal rugae was observed in both Wise and Lrp4 mutant mice, and these mutants also showed the downregulation of Shh signaling, which was accompanied with upregulation of Fgf signaling. Wise and Lrp4 are thus likely to control palatal rugae development by regulating reaction-diffusion mechanisms through Shh and Fgf signaling. We also found that Bmp and Wnt signaling were partially involved in this mechanism.

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          Most cited references43

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          Reaction-diffusion model as a framework for understanding biological pattern formation.

          The Turing, or reaction-diffusion (RD), model is one of the best-known theoretical models used to explain self-regulated pattern formation in the developing animal embryo. Although its real-world relevance was long debated, a number of compelling examples have gradually alleviated much of the skepticism surrounding the model. The RD model can generate a wide variety of spatial patterns, and mathematical studies have revealed the kinds of interactions required for each, giving this model the potential for application as an experimental working hypothesis in a wide variety of morphological phenomena. In this review, we describe the essence of this theory for experimental biologists unfamiliar with the model, using examples from experimental studies in which the RD model is effectively incorporated.
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            LDL-receptor-related proteins in Wnt signal transduction.

            The Wnt family of secreted signalling molecules are essential in embryo development and tumour formation. The Frizzled (Fz) family of serpentine receptors function as Wnt receptors, but how Fz proteins transduce signalling is not understood. In Drosophila, arrow phenocopies the wingless (DWnt-1) phenotype, and encodes a transmembrane protein that is homologous to two members of the mammalian low-density lipoprotein receptor (LDLR)-related protein (LRP) family, LRP5 and LRP6 (refs 12-15). Here we report that LRP6 functions as a co-receptor for Wnt signal transduction. In Xenopus embryos, LRP6 activated Wnt-Fz signalling, and induced Wnt responsive genes, dorsal axis duplication and neural crest formation. An LRP6 mutant lacking the carboxyl intracellular domain blocked signalling by Wnt or Wnt-Fz, but not by Dishevelled or beta-catenin, and inhibited neural crest development. The extracellular domain of LRP6 bound Wnt-1 and associated with Fz in a Wnt-dependent manner. Our results indicate that LRP6 may be a component of the Wnt receptor complex.
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              WNT and DKK determine hair follicle spacing through a reaction-diffusion mechanism.

              Mathematical reaction-diffusion models have been suggested to describe formation of animal pigmentation patterns and distribution of epidermal appendages. However, the crucial signals and in vivo mechanisms are still elusive. Here we identify WNT and its inhibitor DKK as primary determinants of murine hair follicle spacing, using a combined experimental and computational modeling approach. Transgenic DKK overexpression reduces overall appendage density. Moderate suppression of endogenous WNT signaling forces follicles to form clusters during an otherwise normal morphogenetic program. These results confirm predictions of a WNT/DKK-specific mathematical model and provide in vivo corroboration of the reaction-diffusion mechanism for epidermal appendage formation.
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                Author and article information

                Contributors
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Resources
                Role: Resources
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                Role: Investigation
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: SupervisionRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                20 September 2018
                2018
                : 13
                : 9
                : e0204126
                Affiliations
                [1 ] Division of Oral Anatomy, Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
                [2 ] Centre for Craniofacial Development and Regeneration, Dental Institute, King's College London, Guy's Hospital, London, United Kingdom
                [3 ] Research Center for Advanced Oral Science, Department of Oral Life Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
                [4 ] Laboratory of Food Biological Science, Department of Food and Nutrition, Japan Women’s University, Bunkyo, Japan
                [5 ] Department of Neurology, Northwestern University, Feinberg Medical School, Chicago, IL, United States of America
                [6 ] Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, United States of America
                Laboratoire de Biologie du Développement de Villefranche-sur-Mer, FRANCE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-3496-0347
                Article
                PONE-D-18-00529
                10.1371/journal.pone.0204126
                6147471
                30235284
                2187f344-633c-4dee-a4da-aa00a9b9d3a8
                © 2018 Kawasaki 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
                : 6 January 2018
                : 3 September 2018
                Page count
                Figures: 10, Tables: 0, Pages: 17
                Funding
                Funded by: the Japan Society for the Promotion of Science
                Award ID: JSPS; 17H06278)
                Award Recipient :
                This research was funded by the Japan Society for the Promotion of Science (JSPS; 17H06278).
                Categories
                Research Article
                Biology and life sciences
                Cell biology
                Signal transduction
                Cell signaling
                BMP signaling
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Signaling Cascades
                WNT Signaling Cascade
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Biology and Life Sciences
                Anatomy
                Digestive System
                Teeth
                Medicine and Health Sciences
                Anatomy
                Digestive System
                Teeth
                Biology and Life Sciences
                Anatomy
                Head
                Jaw
                Teeth
                Medicine and Health Sciences
                Anatomy
                Head
                Jaw
                Teeth
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Developmental Signaling
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Probe Techniques
                Probe Hybridization
                In Situ Hybridization
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Probe Techniques
                Probe Hybridization
                In Situ Hybridization
                Biology and Life Sciences
                Anatomy
                Digestive System
                Mouth
                Palate
                Medicine and Health Sciences
                Anatomy
                Digestive System
                Mouth
                Palate
                Biology and Life Sciences
                Developmental Biology
                Organism Development
                Organogenesis
                Custom metadata
                All relevant data are within the paper.

                Uncategorized
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