{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:05:26Z","timestamp":1782281126876,"version":"3.54.5"},"posted":{"date-parts":[[2025,8,28]]},"group-title":"Developmental Biology","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"crossref","award":["R01AR070432"],"award-info":[{"award-number":["R01AR070432"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy caused by aberrant expression of the\n                  <jats:italic>DUX4<\/jats:italic>\n                  retrogene, and it affects skeletal muscles primarily in the face, shoulder, and limbs. In healthy individuals,\n                  <jats:italic>DUX4<\/jats:italic>\n                  is expressed in early development and is subsequently silenced in most somatic tissues. The spatiotemporal pattern of DUX4 mis-expression beyond the cleavage stage in FSHD is poorly understood because\n                  <jats:italic>DUX4<\/jats:italic>\n                  is not well conserved beyond primates. Here, we generated Cre reporter mouse lines with human\n                  <jats:italic>DUX4<\/jats:italic>\n                  regulatory elements to investigate the cell lineages derived from\n                  <jats:italic>DUX4<\/jats:italic>\n                  -expressing cells in embryos and adults. Intriguingly, we found that\n                  <jats:italic>DUX4<\/jats:italic>\n                  -expressing cell lineages were present in embryonic forelimb, hindlimb, and face. In adults, the reporter was expressed strongly in testis and to a lesser extent in other tissues, including weak, sporadic expression in skeletal muscles, reminiscent of mosaic DUX4 expression in FSHD. Within skeletal muscles, DUX4 lineage cells include pericytes, an interstitial cell that contributes to muscle regeneration and repair. Overall, this study introduces a new research tool for the field, and provides new insight into potential developmental mechanisms underlying FSHD pathophysiology.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary statement<\/jats:title>\n                  <jats:p>\n                    Cre reporter mouse lines with human\n                    <jats:italic>DUX4<\/jats:italic>\n                    regulatory elements are discovery tools for developmental processes and mechanisms underlying FSHD pathophysiology.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.08.22.671867","type":"posted-content","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T01:30:14Z","timestamp":1756431014000},"source":"Crossref","is-referenced-by-count":0,"title":["Transgenic mouse models for investigating human\n                  <i>DUX4<\/i>\n                  expression during development and its roles in FSHD pathophysiology"],"prefix":"10.64898","author":[{"given":"Yosuke","family":"Hiramuki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charis L.","family":"Himeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter L.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takako I.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025090215201073000_2025.08.22.671867v1.1","doi-asserted-by":"crossref","first-page":"2124","DOI":"10.1093\/hmg\/ddaa079","article-title":"PAX7 target gene repression associates with FSHD progression and pathology over 1 year","volume":"29","year":"2020","journal-title":"Hum Mol Genet"},{"key":"2025090215201073000_2025.08.22.671867v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00730-1"},{"key":"2025090215201073000_2025.08.22.671867v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-35150-8"},{"key":"2025090215201073000_2025.08.22.671867v1.4","doi-asserted-by":"crossref","unstructured":"Bosnakovski, D. , Oyler, D. , Mitanoska, A. , Douglas, M. , Ener, E. T. , Shams, A. S. and Kyba, M . (2022). Persistent Fibroadipogenic Progenitor Expansion Following Transient DUX4 Expression Provokes a Profibrotic State in a Mouse Model for FSHD. Int J Mol Sci 23.","DOI":"10.3390\/ijms23041983"},{"key":"2025090215201073000_2025.08.22.671867v1.5","doi-asserted-by":"publisher","DOI":"10.1242\/dev.151035"},{"key":"2025090215201073000_2025.08.22.671867v1.6","doi-asserted-by":"crossref","unstructured":"Chen, T. H. , Wu, Y. Z. and Tseng, Y. H . (2020). Early-Onset Infantile Facioscapulohumeral Muscular Dystrophy: A Timely Review. Int J Mol Sci 21.","DOI":"10.3390\/ijms21207783"},{"key":"2025090215201073000_2025.08.22.671867v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/nature13985"},{"key":"2025090215201073000_2025.08.22.671867v1.8","doi-asserted-by":"publisher","DOI":"10.1086\/519311"},{"key":"2025090215201073000_2025.08.22.671867v1.9","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21091"},{"key":"2025090215201073000_2025.08.22.671867v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3858"},{"key":"2025090215201073000_2025.08.22.671867v1.11","doi-asserted-by":"crossref","unstructured":"de la Kethulle de Ryhove, L. , Ansseau, E. , Nachtegael, C. , Pieters, K. , Vanderplanck, C. , Geens, M. , Sermon, K. , Wilton, S. D. , Coppee, F. , Lagneaux, L. , et al. (2015). The Role of D4Z4-Encoded Proteins in the Osteogenic Differentiation of Mesenchymal Stromal Cells Isolated from Bone Marrow. Stem Cells Dev.","DOI":"10.1089\/scd.2014.0575"},{"key":"2025090215201073000_2025.08.22.671867v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2959"},{"key":"2025090215201073000_2025.08.22.671867v1.13","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000797"},{"key":"2025090215201073000_2025.08.22.671867v1.14","doi-asserted-by":"crossref","unstructured":"Deenen, J. C. , Verbeek, A. L. , Verschuuren, J. J. , van Engelen, B. G. and Voermans, N. C. (2025). Prevalence and incidence rates of 17 neuromuscular disorders: An updated review of the literature. J Neuromuscul Dis, 22143602241313118.","DOI":"10.1177\/22143602241313118"},{"key":"2025090215201073000_2025.08.22.671867v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1508"},{"key":"2025090215201073000_2025.08.22.671867v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1542"},{"key":"2025090215201073000_2025.08.22.671867v1.17","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky018"},{"key":"2025090215201073000_2025.08.22.671867v1.18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0708659104"},{"key":"2025090215201073000_2025.08.22.671867v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/S1567-133X(03)00084-X"},{"key":"2025090215201073000_2025.08.22.671867v1.20","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt409"},{"key":"2025090215201073000_2025.08.22.671867v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(99)00267-X"},{"key":"2025090215201073000_2025.08.22.671867v1.22","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1016\/j.jid.2016.01.027","article-title":"DUX4 Is Derepressed in Late-Differentiating Keratinocytes in Conjunction with Loss of H3K9me3 Epigenetic Repression","volume":"136","year":"2016","journal-title":"J Invest Dermatol"},{"key":"2025090215201073000_2025.08.22.671867v1.23","doi-asserted-by":"crossref","first-page":"433","DOI":"10.3389\/fncel.2019.00433","article-title":"Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy","volume":"13","year":"2019","journal-title":"Front Cell Neurosci"},{"key":"2025090215201073000_2025.08.22.671867v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2017.09.007"},{"key":"2025090215201073000_2025.08.22.671867v1.25","doi-asserted-by":"publisher","DOI":"10.1186\/s13072-018-0215-z"},{"key":"2025090215201073000_2025.08.22.671867v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3844"},{"key":"2025090215201073000_2025.08.22.671867v1.27","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00149-14"},{"key":"2025090215201073000_2025.08.22.671867v1.28","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-083118-014933"},{"key":"2025090215201073000_2025.08.22.671867v1.29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0192657"},{"key":"2025090215201073000_2025.08.22.671867v1.30","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds284"},{"key":"2025090215201073000_2025.08.22.671867v1.31","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-015-0072-6"},{"key":"2025090215201073000_2025.08.22.671867v1.32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0150938"},{"key":"2025090215201073000_2025.08.22.671867v1.33","doi-asserted-by":"publisher","DOI":"10.1186\/1868-7083-6-23"},{"key":"2025090215201073000_2025.08.22.671867v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2006.06.008"},{"key":"2025090215201073000_2025.08.22.671867v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2007.04.002"},{"key":"2025090215201073000_2025.08.22.671867v1.36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003415"},{"key":"2025090215201073000_2025.08.22.671867v1.37","doi-asserted-by":"publisher","DOI":"10.1007\/s00412-012-0380-y"},{"key":"2025090215201073000_2025.08.22.671867v1.38","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2148-10-364"},{"key":"2025090215201073000_2025.08.22.671867v1.39","doi-asserted-by":"publisher","DOI":"10.1126\/science.1189044"},{"key":"2025090215201073000_2025.08.22.671867v1.40","doi-asserted-by":"publisher","DOI":"10.1242\/dev.050674"},{"key":"2025090215201073000_2025.08.22.671867v1.41","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp698"},{"key":"2025090215201073000_2025.08.22.671867v1.42","doi-asserted-by":"crossref","unstructured":"Lim, K. R. Q. , Nguyen, Q. and Yokota, T . (2020). DUX4 Signalling in the Pathogenesis of Facioscapulohumeral Muscular Dystrophy. Int J Mol Sci 21.","DOI":"10.3390\/ijms21030729"},{"key":"2025090215201073000_2025.08.22.671867v1.43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0610155104"},{"key":"2025090215201073000_2025.08.22.671867v1.44","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/27.19.e27"},{"key":"2025090215201073000_2025.08.22.671867v1.45","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds467"},{"key":"2025090215201073000_2025.08.22.671867v1.46","first-page":"1735","article-title":"Facioscapulohumeral Muscular Dystrophy","volume":"28","year":"2022","journal-title":"Continuum (Minneap Minn"},{"key":"2025090215201073000_2025.08.22.671867v1.47","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddad021"},{"key":"2025090215201073000_2025.08.22.671867v1.48","unstructured":"Orphanet. (2024). Prevalence and incidence of rare diseases: Bibliographic data. In Orphanet Report Series: Rare Diseases collection: Inserm."},{"key":"2025090215201073000_2025.08.22.671867v1.49","doi-asserted-by":"publisher","DOI":"10.4161\/nucl.1.1.10799"},{"key":"2025090215201073000_2025.08.22.671867v1.50","unstructured":"Padberg, G. W. (1982). Facioscapulohumeral Disease [thesis], pp. 243. Leiden, the Netherlands: Leiden University."},{"key":"2025090215201073000_2025.08.22.671867v1.51","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy348"},{"key":"2025090215201073000_2025.08.22.671867v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.10.025"},{"key":"2025090215201073000_2025.08.22.671867v1.53","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv315"},{"key":"2025090215201073000_2025.08.22.671867v1.54","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00066-0"},{"key":"2025090215201073000_2025.08.22.671867v1.55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1001181"},{"key":"2025090215201073000_2025.08.22.671867v1.56","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2012.01647.x"},{"key":"2025090215201073000_2025.08.22.671867v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(24)00073-5"},{"key":"2025090215201073000_2025.08.22.671867v1.58","doi-asserted-by":"publisher","DOI":"10.1172\/JCI89401"},{"key":"2025090215201073000_2025.08.22.671867v1.59","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/2.12.2037"},{"key":"2025090215201073000_2025.08.22.671867v1.60","doi-asserted-by":"publisher","DOI":"10.1038\/ng1262"},{"key":"2025090215201073000_2025.08.22.671867v1.61","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1307680110"},{"key":"2025090215201073000_2025.08.22.671867v1.62","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22275"},{"key":"2025090215201073000_2025.08.22.671867v1.63","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3265"},{"key":"2025090215201073000_2025.08.22.671867v1.64","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3846"},{"key":"2025090215201073000_2025.08.22.671867v1.65","first-page":"411","article-title":"Genetic linkage map of facioscapulohumeral muscular dystrophy and five polymorphic loci on chromosome 4q35-qter","volume":"51","year":"1992","journal-title":"Am J Hum Genet"},{"key":"2025090215201073000_2025.08.22.671867v1.66","doi-asserted-by":"crossref","unstructured":"Wong, C. J. , Friedman, S. D. , Snider, L. , Bennett, S. R. , Jones, T. I. , Jones, P. L. , Shaw, D. W. W. , Blemker, S. S. , Riem, L. , DuCharme, O. et al. (2024). Regional and bilateral MRI and gene signatures in facioscapulohumeral dystrophy: implications for clinical trial design and mechanisms of disease progression. Hum Mol Genet.","DOI":"10.1093\/hmg\/ddae007"},{"key":"2025090215201073000_2025.08.22.671867v1.67","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddaa031"},{"key":"2025090215201073000_2025.08.22.671867v1.68","first-page":"386","article-title":"Testing the effects of FSHD candidate gene expression in vertebrate muscle development","volume":"3","year":"2010","journal-title":"Int J Clin Exp Pathol"},{"key":"2025090215201073000_2025.08.22.671867v1.69","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20474"},{"key":"2025090215201073000_2025.08.22.671867v1.70","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu251"},{"key":"2025090215201073000_2025.08.22.671867v1.71","doi-asserted-by":"publisher","DOI":"10.1006\/excr.2002.5653"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.08.22.671867","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:15:13Z","timestamp":1782278113000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.08.22.671867"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,28]]},"references-count":71,"URL":"https:\/\/doi.org\/10.1101\/2025.08.22.671867","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1242\/dmm.052637","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,8,28]]},"subtype":"preprint"}}