{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:00Z","timestamp":1787027820400,"version":"build-2736575974"},"reference-count":39,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T00:00:00Z","timestamp":1748044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NHLBI","award":["HL131546"],"award-info":[{"award-number":["HL131546"]}]},{"name":"NIH\/NHLBI","award":["HL149696"],"award-info":[{"award-number":["HL149696"]}]},{"name":"NIH\/NHLBI","award":["HL173930"],"award-info":[{"award-number":["HL173930"]}]},{"name":"NIH\/NHLBI","award":["24TPA1304545"],"award-info":[{"award-number":["24TPA1304545"]}]},{"name":"AHA","award":["HL131546"],"award-info":[{"award-number":["HL131546"]}]},{"name":"AHA","award":["HL149696"],"award-info":[{"award-number":["HL149696"]}]},{"name":"AHA","award":["HL173930"],"award-info":[{"award-number":["HL173930"]}]},{"name":"AHA","award":["24TPA1304545"],"award-info":[{"award-number":["24TPA1304545"]}]},{"name":"Leducq Foundation","award":["HL131546"],"award-info":[{"award-number":["HL131546"]}]},{"name":"Leducq Foundation","award":["HL149696"],"award-info":[{"award-number":["HL149696"]}]},{"name":"Leducq Foundation","award":["HL173930"],"award-info":[{"award-number":["HL173930"]}]},{"name":"Leducq Foundation","award":["24TPA1304545"],"award-info":[{"award-number":["24TPA1304545"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Intercellular interactions among cardiac cell populations are essential for cardiac morphogenesis, yet the molecular mechanisms orchestrating these events remain incompletely understood. Dachsous1 (Dchs1), an atypical cadherin linked to mitral valve prolapse, is a core planar cell polarity protein whose function in the developing heart has not been fully elucidated. To address this, we generated a Dchs1-HA knock-in mouse model to define its spatial, temporal, and cellular expression patterns. Using immunohistochemistry, western blotting, and single-cell transcriptomics across developmental stages, we demonstrate that cardiac Dchs1 expression is restricted to non-cardiomyocyte lineages. DCHS1 displays dynamic subcellular localization and tissue organization depending on the developmental timepoint, with staining being found in epicardial and endocardial surfaces at earlier embryonic stages and in the compact myocardium in later fetal and neonatal stages. During fetal and neonatal stages, DCHS1-positive non-myocyte, non-endothelial cells form polarized extensions that bridge endothelial and non-myocyte, non-endothelial cells, suggesting direct heterotypic and homotypic interactions. Western blotting revealed evidence of DCHS1 proteolytic cleavage, with intracellular C-terminal fragments. RNA co-expression with its binding partner FAT4 supports a conserved, non-myocyte-specific DCHS1-FAT4 signaling axis. These findings identify DCHS1 as a potential molecular tether that is utilized in intercellular communications during cardiac development, with implications for congenital and acquired heart disease.<\/jats:p>","DOI":"10.3390\/cells14110774","type":"journal-article","created":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T20:39:36Z","timestamp":1748205576000},"page":"774","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Dynamic Expression and Functional Implications of the Cell Polarity Gene, Dchs1, During Cardiac Development"],"prefix":"10.3390","volume":"14","author":[{"given":"Kathryn","family":"Byerly","sequence":"first","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29407, 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(2022). ETS1 and HLHS: Implications for the Role of the Endocardium. J. Cardiovasc. Dev. Dis., 9.","DOI":"10.3390\/jcdd9070219"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1007\/978-3-031-44087-8_36","article-title":"Human Genetics of Tetralogy of Fallot and Double-Outlet Right Ventricle","volume":"1441","author":"Dorn","year":"2024","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"101890","DOI":"10.1016\/j.arr.2023.101890","article-title":"Sinus node dysfunction and atrial fibrillation-Relationships, clinical phenotypes, new mechanisms, and treatment approaches","volume":"86","author":"Duan","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bazgir, F., Nau, J., Nakhaei-Rad, S., Amin, E., Wolf, M.J., Saucerman, J.J., Lorenz, K., and Ahmadian, M.R. (2023). The Microenvironment of the Pathogenesis of Cardiac Hypertrophy. Cells, 12.","DOI":"10.3390\/cells12131780"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1007\/s00246-019-02151-x","article-title":"Long QT Syndrome: Genetics and Future Perspective","volume":"40","author":"Wallace","year":"2019","journal-title":"Pediatr. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1089\/ten.teb.2014.0662","article-title":"Signaling Pathways and Gene Regulatory Networks in Cardiomyocyte Differentiation","volume":"21","author":"Parikh","year":"2015","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1007\/s00018-022-04620-8","article-title":"Wnt\/planar cell polarity signaling controls morphogenetic movements of gastrulation and neural tube closure","volume":"79","author":"Shi","year":"2022","journal-title":"Cell Mol. Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.devcel.2020.02.003","article-title":"Hedgehog-Activated Fat4 and PCP Pathways Mediate Mesenchymal Cell Clustering and Villus Formation in Gut Development","volume":"52","author":"Zhu","year":"2020","journal-title":"Dev. Cell."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/bs.ctdb.2022.03.006","article-title":"Wnt-frizzled planar cell polarity signaling in the regulation of cell motility","volume":"150","author":"Koca","year":"2022","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1126\/science.1199010","article-title":"Hippo Pathway Inhibits Wnt Signaling to Restrain Cardiomyocyte Proliferation and Heart Size","volume":"332","author":"Heallen","year":"2011","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.gendis.2023.01.030","article-title":"Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk","volume":"11","author":"Qin","year":"2024","journal-title":"Genes. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jgg.2022.06.007","article-title":"Planar cell polarity regulators in asymmetric organogenesis during development and disease","volume":"50","author":"Shi","year":"2023","journal-title":"J. Genet. Genom."},{"key":"ref_13","first-page":"2574","article-title":"Fat4\/Dchs1 signaling between stromal and cap mesenchyme cells influences nephrogenesis and ureteric bud branching","volume":"142","author":"Mao","year":"2015","journal-title":"Development"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"11469","DOI":"10.1038\/ncomms11469","article-title":"Dchs1-Fat4 regulation of polarized cell behaviours during skeletal morphogenesis","volume":"7","author":"Mao","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1083\/jcb.200811030","article-title":"Mammalian Fat and Dachsous cadherins regulate apical membrane organization in the embryonic cerebral cortex","volume":"185","author":"Ishiuchi","year":"2009","journal-title":"J. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1242\/dev.131037","article-title":"Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae","volume":"143","author":"Kuta","year":"2016","journal-title":"Development"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/nature14670","article-title":"Mutations in DCHS1 cause mitral valve prolapse","volume":"525","author":"Durst","year":"2015","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Moore, K.S., Moore, R., Fulmer, D.B., Guo, L., Gensemer, C., Stairley, R., Glover, J., Beck, T.C., Morningstar, J.E., and Biggs, R. (2022). DCHS1, Lix1L, and the Septin Cytoskeleton: Molecular and Developmental Etiology of Mitral Valve Prolapse. J. Cardiovasc. Dev. Dis., 9.","DOI":"10.3390\/jcdd9020062"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1136\/jmg-2023-109278","article-title":"Mutation in mitral valve prolapse susceptible gene DCHS1 causes familial mitral annular disjunction","volume":"61","author":"Zhou","year":"2024","journal-title":"J. Med. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1016\/j.cub.2014.05.067","article-title":"Regulation of neuronal migration by Dchs1-Fat4 planar cell polarity","volume":"24","author":"Zakaria","year":"2014","journal-title":"Curr. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"dev176776","DOI":"10.1242\/dev.176776","article-title":"Dchs1-Fat4 regulation of osteogenic differentiation in mouse","volume":"146","author":"Hodgson","year":"2019","journal-title":"Development"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/dvdy.21378","article-title":"Differential growth and multicellular villi direct proepicardial translocation to the developing mouse heart","volume":"237","author":"Rodgers","year":"2008","journal-title":"Dev. Dyn."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.yjmcc.2023.11.002","article-title":"Epicardial deletion of Sox9 leads to myxomatous valve degeneration and identifies Cd109 as a novel gene associated with valve development","volume":"186","author":"Harvey","year":"2024","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/pr.2014.128","article-title":"A detailed comparison of mouse and human cardiac development","volume":"76","author":"Krishnan","year":"2014","journal-title":"Pediatr. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/ncb3149","article-title":"ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation","volume":"17","author":"Aharonov","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1038\/s41592-023-01943-7","article-title":"Unsupervised removal of systematic background noise from droplet-based single-cell experiments using CellBender","volume":"20","author":"Fleming","year":"2023","journal-title":"Nat. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with Harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nature Methods."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41592-019-0654-x","article-title":"Orchestrating single-cell analysis with Bioconductor","volume":"17","author":"Amezquita","year":"2020","journal-title":"Nat. Methods"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"979","DOI":"10.12688\/f1000research.73600.1","article-title":"Doublet identification in single-cell sequencing data using scDblFinder","volume":"10","author":"Germain","year":"2021","journal-title":"F1000Research"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e80479","DOI":"10.7554\/eLife.80479","article-title":"Single-cell RNA-seq of heart reveals intercellular communication drivers of myocardial fibrosis in diabetic cardiomyopathy","volume":"12","author":"Li","year":"2023","journal-title":"eLife"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/s41597-023-02333-6","article-title":"Single-cell RNA sequencing of murine hearts for studying the development of the cardiac conduction system","volume":"10","author":"Ren","year":"2023","journal-title":"Sci. Data"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Jiang, H., Lei, R., Ding, S.-W., and Zhu, S. (2014). Skewer: A fast and accurate adapter trimmer for next-generation sequencing paired-end reads. BMC Bioinform., 15.","DOI":"10.1186\/1471-2105-15-182"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"The Tabula Muris Consortium, Overall Coordination, Logistical Coordination, Organ Collection and Processing, Library Preparation and Sequencing, Computational Data Analysis, Cell Type Annotation, Writing Group, Supplemental Text Writing Group, and Principal Investigators (2018). Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature, 562, 367\u2013372.","DOI":"10.1038\/s41586-018-0590-4"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1242\/dev.057166","article-title":"Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development","volume":"138","author":"Mao","year":"2011","journal-title":"Development"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1038\/s41467-023-36435-x","article-title":"Structure of the planar cell polarity cadherins Fat4 and Dachsous1","volume":"14","author":"Medina","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/s41569-018-0100-2","article-title":"Notch and interacting signalling pathways in cardiac development, disease, and regeneration","volume":"15","author":"MacGrogan","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_38","first-page":"e1","article-title":"Endocardial Notch Signaling in Cardiac Development and Disease","volume":"118","author":"MacGrogan","year":"2016","journal-title":"Circ. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1111\/j.1749-6632.2009.05099.x","article-title":"Notch and cardiac outflow tract development","volume":"1188","author":"Jain","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/11\/774\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:39:36Z","timestamp":1760031576000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/11\/774"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,24]]},"references-count":39,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["cells14110774"],"URL":"https:\/\/doi.org\/10.3390\/cells14110774","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,24]]}}}