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      Expression patterns of ciliopathy genes ARL3 and CEP120 reveal roles in multisystem development

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          Abstract

          Background

          Joubert syndrome and related disorders (JSRD) and Jeune syndrome are multisystem ciliopathy disorders with overlapping phenotypes. There are a growing number of genetic causes for these rare syndromes, including the recently described genes ARL3 and CEP120.

          Methods

          We sought to explore the developmental expression patterns of ARL3 and CEP120 in humans to gain additional understanding of these genetic conditions. We used an RNA in situ detection technique called RNAscope to characterise ARL3 and CEP120 expression patterns in human embryos and foetuses in collaboration with the MRC-Wellcome Trust Human Developmental Biology Resource.

          Results

          Both ARL3 and CEP120 are expressed in early human brain development, including the cerebellum and in the developing retina and kidney, consistent with the clinical phenotypes seen with pathogenic variants in these genes.

          Conclusions

          This study provides insights into the potential pathogenesis of JSRD by uncovering the spatial expression of two JSRD-causative genes during normal human development.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12861-020-00231-3.

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          Most cited references49

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          RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues.

          In situ analysis of biomarkers is highly desirable in molecular pathology because it allows the examination of biomarker status within the histopathological context of clinical specimens. Immunohistochemistry and DNA in situ hybridization (ISH) are widely used in clinical settings to assess protein and DNA biomarkers, respectively, but clinical use of in situ RNA analysis is rare. This disparity is especially notable when considering the abundance of RNA biomarkers discovered through whole-genome expression profiling. This is largely due to the high degree of technical complexity and insufficient sensitivity and specificity of current RNA ISH techniques. Here, we describe RNAscope, a novel RNA ISH technology with a unique probe design strategy that allows simultaneous signal amplification and background suppression to achieve single-molecule visualization while preserving tissue morphology. RNAscope is compatible with routine formalin-fixed, paraffin-embedded tissue specimens and can use either conventional chromogenic dyes for bright-field microscopy or fluorescent dyes for multiplex analysis. Unlike grind-and-bind RNA analysis methods such as real-time RT-PCR, RNAscope brings the benefits of in situ analysis to RNA biomarkers and may enable rapid development of RNA ISH-based molecular diagnostic assays. Copyright © 2012 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.
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            Genes and molecular pathways underpinning ciliopathies

            Motile and non-motile primary cilia are nearly ubiquitous cellular organelles. Dysfunction of cilia is being found to cause increasing numbers of diseases that are known as ciliopathies. The characterization of ciliopathy-associated proteins and phenotypes is increasing our understanding of how cilia are formed and compartmentalized and how they function to maintain human health.
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              The Cilium: Cellular Antenna and Central Processing Unit

              Cilia mediate an astonishing diversity of processes. Recent advances provide unexpected insights into the regulatory mechanisms of cilium formation, and reveal diverse regulatory inputs that are related to the cell cycle, cytoskeleton, proteostasis, and cilia-mediated signaling itself. Ciliogenesis and cilia maintenance are regulated by reciprocal antagonistic or synergistic influences, often acting in parallel to each other. By receiving parallel inputs, cilia appear to integrate multiple signals into specific outputs and may have functions similar to logic gates of digital systems. Some combinations of input signals appear to impose higher hierarchical control related to the cell cycle. An integrated view of these regulatory inputs will be necessary to understand ciliogenesis and its wider relevance to human biology.
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                Author and article information

                Contributors
                john.sayer@newcastle.ac.uk
                Journal
                BMC Dev Biol
                BMC Dev Biol
                BMC Developmental Biology
                BioMed Central (London )
                1471-213X
                9 December 2020
                9 December 2020
                2020
                : 20
                : 26
                Affiliations
                [1 ]GRID grid.1006.7, ISNI 0000 0001 0462 7212, Translational and Clinical Research Institute, , Newcastle University, ; Central Parkway, Newcastle upon Tyne, NE1 3BZ UK
                [2 ]GRID grid.1006.7, ISNI 0000 0001 0462 7212, Biosciences Institute, , Newcastle University, ; Framlington Place, Newcastle upon Tyne, NE2 4HH UK
                [3 ]GRID grid.420004.2, ISNI 0000 0004 0444 2244, The Newcastle Hospitals NHS Foundation Trust, ; Freeman Road, Newcastle upon Tyne, NE7 7DN UK
                [4 ]National Institute for Health Research Newcastle Biomedical Research Centre, Newcastle upon Tyne, NE4 5PL UK
                Author information
                http://orcid.org/0000-0003-1881-3782
                Article
                231
                10.1186/s12861-020-00231-3
                7727171
                33297941
                596fd385-ae1a-4b6c-b5e4-63e79fab420e
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 27 July 2020
                : 11 November 2020
                Funding
                Funded by: Medical Research Council
                Funded by: Kidney Research UK
                Award ID: ST_001_20171120
                Award ID: PDF_003_20151124
                Award ID: Paed_RP_20180925
                Funded by: FundRef http://dx.doi.org/10.13039/501100004185, Northern Counties Kidney Research Fund;
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2020

                Developmental biology
                cep120,arl3,foetus,development,retina,kidney,brain,rnascope
                Developmental biology
                cep120, arl3, foetus, development, retina, kidney, brain, rnascope

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