Topic
DCHS1
About: DCHS1 is a research topic. Over the lifetime, 11 publications have been published within this topic receiving 471 citations. The topic is also known as: CDH19 & CDH25.
Papers
Harvard University1, Hebrew University of Jerusalem2, Medical University of South Carolina3, French Institute of Health and Medical Research4, Paris Descartes University5, Beth Israel Deaconess Medical Center6, Yale University7, Centro Nacional de Investigaciones Cardiovasculares8, Pompeu Fabra University9, National Institutes of Health10, Rutgers University11, Aix-Marseille University12, University of Texas Health Science Center at San Antonio13, University of Paris14
TL;DR: A missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the family is reported, supporting these processes as aetiological underpinnings for the disease.
Abstract: Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic aetiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the family. Morpholino knockdown of the zebrafish homologue dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 messenger RNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1(+/-) mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs, as well as in Dchs1(+/-) mouse MVICs, result in altered migration and cellular patterning, supporting these processes as aetiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.
151 citations
TL;DR: The ubiquitous expression of ft in several tissues in Drosophila appears to be split into an epithelial expression of fat1/fat3 and a mesenchymal expression offat‐j, which is compatible with a conservation and subfunctionalization of the Dosophila Ds, Fj, and Fat signaling in higher vertebrates.
Abstract: The dachsous (ds), fat (ft), and four-jointed (fj) genes have been identified in Drosophila as part of a signaling pathway that regulates planar cell polarity (PCP). A homologous PCP signaling pathway has also been identified in vertebrates, but nothing is known thus far about the conservation of Ds/Ft/Fj signaling. Here we analyzed and compared for the first time the expression patterns of all ds, ft and fj homologs in the mouse. During embryogenesis, expression analysis was performed by RNA in situ hybridization and in adult organs by real time PCR. As in Drosophila, we detected a complementary expression of fjx1 and dchs1 in organs like kidney, lung, and intestine. The ubiquitous expression of ft in several tissues in Drosophila appears to be split into an epithelial expression of fat1/fat3 and a mesenchymal expression of fat-j. These data are compatible with a conservation and sub-functionalization of the Drosophila Ds, Fj, and Fat signaling in higher vertebrates.
103 citations
TL;DR: The results indicate novel roles for vertebrate Dchs in actin and microtubule cytoskeleton regulation in the unanticipated context of the single-celled embryo.
Abstract: Dachsous (Dchs), an atypical cadherin, is an evolutionarily conserved regulator of planar cell polarity, tissue size and cell adhesion. In humans, DCHS1 mutations cause pleiotropic Van Maldergem syndrome. Here, we report that mutations in zebrafish dchs1b and dchs2 disrupt several aspects of embryogenesis, including gastrulation. Unexpectedly, maternal zygotic (MZ) dchs1b mutants show defects in the earliest developmental stage, egg activation, including abnormal cortical granule exocytosis (CGE), cytoplasmic segregation, cleavages and maternal mRNA translocation, in transcriptionally quiescent embryos. Later, MZdchs1b mutants exhibit altered dorsal organizer and mesendodermal gene expression, due to impaired dorsal determinant transport and Nodal signaling. Mechanistically, MZdchs1b phenotypes can be explained in part by defective actin or microtubule networks, which appear bundled in mutants. Accordingly, disruption of actin cytoskeleton in wild-type embryos phenocopied MZdchs1b mutant defects in cytoplasmic segregation and CGE, whereas interfering with microtubules in wild-type embryos impaired dorsal organizer and mesodermal gene expression without perceptible earlier phenotypes. Moreover, the bundled microtubule phenotype was partially rescued by expressing either full-length Dchs1b or its intracellular domain, suggesting that Dchs1b affects microtubules and some developmental processes independent of its known ligand Fat. Our results indicate novel roles for vertebrate Dchs in actin and microtubule cytoskeleton regulation in the unanticipated context of the single-celled embryo.
42 citations
TL;DR: It is shown that Dchs1 is ubiquitously expressed in mouse embryos, but exhibits a highly restricted expression to lung tissues in the adult stage, which suggests a specific role of D chs1 in PCP-dependent organization of ciliary function and a possible role in lung disease.
11 citations
1 Jan 2016
TL;DR: How the atypical cadherins control cell behaviors with the emphasis on one particular orchestration of cells along the axes of tissues, organs, or bodies, inclusively designated as planar cell polarity (PCP) is discussed.
Abstract: In this chapter, two subfamilies of atypical cadherins are described: the subfamily of seven-pass transmembrane cadherins (7-TM cadherins) and Fat and Dachsous cadherins. Pioneering genetic studies in Drosophila have defined both subfamilies and dissected their roles in animal development. It is now clear that the founding members in Drosophila and their respective vertebrate homologues make critical and essential contributions to a variety of dynamic behaviors of cell populations, and that malfunctions of those atypical cadherins cause anomalies in embryonic development, resulting in postnatal organ malformation or embryonic demise. Here we discuss how the atypical cadherins control cell behaviors with the emphasis on one particular orchestration of cells along the axes of tissues, organs, or bodies, inclusively designated as planar cell polarity (PCP). Nowadays the purview of PCP ranges from the unidirectional orientation of subcellular structures, such as wing hairs of Drosophila and vertebrate motile cilia, to three-dimensional dynamics of multicellular units, such as tilting hair follicles, neural tube closure, epithelial folding in the oviduct, and collective cell migration. The PCP field is at an extraordinarily exciting juncture, bursting with questions about functions of 7-TM cadherins and Fat and Dachsous cadherins at the cellular and molecular level.
7 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 1 |
| 2018 | 2 |
| 2016 | 2 |
| 2015 | 4 |
| 2011 | 1 |
| 2005 | 1 |