{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:39:36Z","timestamp":1790437176702,"version":"4.1.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,8,7]],"date-time":"2017-08-07T00:00:00Z","timestamp":1502064000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,8,7]],"date-time":"2017-08-07T00:00:00Z","timestamp":1502064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder resulting from mutations in the <jats:italic>dystrophin<\/jats:italic> gene. The <jats:italic>mdx\/utrn<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse, lacking in both dystrophin and its autosomal homologue utrophin, is commonly used to model the clinical symptoms of DMD. Interestingly, these mice are infertile but the mechanisms underlying this phenomenon remain unclear. Using <jats:italic>dystrophin<\/jats:italic> deficient <jats:italic>mdx<\/jats:italic> mouse and <jats:italic>utrophin<\/jats:italic> haplodeficient <jats:italic>mdx\/utrn<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mouse models, we demonstrate the contribution of Dp427 (full-length dystrophin) and utrophin to testis and epididymis development, as well as spermatogenesis. We show that Dp427 deficiency disturbed the balance between proliferation and apoptosis of germ cells during spermatogenesis, which was further disrupted with <jats:italic>utrophin<\/jats:italic> haplodeficiency, deciphering a compensatory role of utrophin for dystrophin in the male reproductive system. In the spermatozoa, we have found a compensatory response of utrophin to dystrophin deficiency - namely the upregulation and relocation of utrophin to the flagellar midpiece. This study demonstrates the contribution of Dp427 and utrophin in male fertility, suggesting a potential pathology in DMD patients.<\/jats:p>","DOI":"10.1038\/s41598-017-05993-8","type":"journal-article","created":{"date-parts":[[2017,8,1]],"date-time":"2017-08-01T07:43:50Z","timestamp":1501573430000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Utrophin Compensates dystrophin Loss during Mouse Spermatogenesis"],"prefix":"10.1038","volume":"7","author":[{"given":"Hung-Chih","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Feng","family":"Chin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Lundy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Tiang","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9216-0938","authenticated-orcid":false,"given":"Ya-Hui","family":"Chi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolin","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8910-3596","authenticated-orcid":false,"given":"Patrick C. H.","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,7]]},"reference":[{"key":"5993_CR1","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/nrg3460","volume":"14","author":"RJ Fairclough","year":"2013","unstructured":"Fairclough, R. J., Wood, M. J. & Davies, K. E. Therapy for Duchenne muscular dystrophy: renewed optimism from genetic approaches. Nat Rev Genet \n                           14, 373\u2013378 (2013).","journal-title":"Nat Rev Genet"},{"key":"5993_CR2","first-page":"835","volume":"45","author":"JT Den Dunnen","year":"1989","unstructured":"Den Dunnen, J. T. et al. Topography of the Duchenne muscular dystrophy (DMD) gene: FIGE and cDNA analysis of 194 cases reveals 115 deletions and 13 duplications. Am J Hum Genet \n                           45, 835\u2013847 (1989).","journal-title":"Am J Hum Genet"},{"key":"5993_CR3","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/0092-8674(87)90504-6","volume":"50","author":"M Koenig","year":"1987","unstructured":"Koenig, M. et al. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell \n                           50, 509\u2013517 (1987).","journal-title":"Cell"},{"key":"5993_CR4","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/0092-8674(88)90383-2","volume":"53","author":"M Koenig","year":"1988","unstructured":"Koenig, M., Monaco, A. P. & Kunkel, L. M. The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein. Cell \n                           53, 219\u2013228 (1988).","journal-title":"Cell"},{"key":"5993_CR5","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1083\/jcb.122.4.809","volume":"122","author":"JM Ervasti","year":"1993","unstructured":"Ervasti, J. M. & Campbell, K. P. A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. J Cell Biol \n                           122, 809\u2013823 (1993).","journal-title":"J Cell Biol"},{"key":"5993_CR6","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/0092-8674(95)90471-9","volume":"82","author":"JE Brenman","year":"1995","unstructured":"Brenman, J. E., Chao, D. S., Xia, H., Aldape, K. & Bredt, D. S. Nitric oxide synthase complexed with dystrophin and absent from skeletal muscle sarcolemma in Duchenne muscular dystrophy. Cell \n                           82, 743\u2013752 (1995).","journal-title":"Cell"},{"key":"5993_CR7","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1038\/nm.3990","volume":"21","author":"NA Dumont","year":"2015","unstructured":"Dumont, N. A. et al. Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division. Nat Med \n                           21, 1455\u20131463 (2015).","journal-title":"Nat Med"},{"key":"5993_CR8","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/S1474-4422(03)00585-4","volume":"2","author":"F Muntoni","year":"2003","unstructured":"Muntoni, F., Torelli, S. & Ferlini, A. Dystrophin and mutations: one gene, several proteins, multiple phenotypes. Lancet Neurol \n                           2, 731\u2013740 (2003).","journal-title":"Lancet Neurol"},{"key":"5993_CR9","doi-asserted-by":"publisher","first-page":"5899","DOI":"10.1074\/jbc.M709410200","volume":"283","author":"PA \u2018t Hoen","year":"2008","unstructured":"\u2018t Hoen, P. A. et al. Generation and characterization of transgenic mice with the full-length human DMD gene. J Biol Chem \n                           283, 5899\u20135907 (2008).","journal-title":"J Biol Chem"},{"key":"5993_CR10","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/339055a0","volume":"339","author":"DR Love","year":"1989","unstructured":"Love, D. R. et al. An autosomal transcript in skeletal muscle with homology to dystrophin. Nature \n                           339, 55\u201358 (1989).","journal-title":"Nature"},{"key":"5993_CR11","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/360591a0","volume":"360","author":"JM Tinsley","year":"1992","unstructured":"Tinsley, J. M. et al. Primary structure of dystrophin-related protein. Nature \n                           360, 591\u2013593 (1992).","journal-title":"Nature"},{"key":"5993_CR12","doi-asserted-by":"publisher","first-page":"3243","DOI":"10.1073\/pnas.88.8.3243","volume":"88","author":"DR Love","year":"1991","unstructured":"Love, D. R. et al. Tissue distribution of the dystrophin-related gene product and expression in the mdx and dy mouse. Proc Natl Acad Sci USA \n                           88, 3243\u20133247 (1991).","journal-title":"Proc Natl Acad Sci USA"},{"key":"5993_CR13","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/0896-6273(91)90301-F","volume":"7","author":"K Ohlendieck","year":"1991","unstructured":"Ohlendieck, K. et al. Dystrophin-related protein is localized to neuromuscular junctions of adult skeletal muscle. Neuron \n                           7, 499\u2013508 (1991).","journal-title":"Neuron"},{"key":"5993_CR14","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1073\/pnas.1013067108","volume":"108","author":"AR Amenta","year":"2011","unstructured":"Amenta, A. R. et al. Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice. Proc Natl Acad Sci USA \n                           108, 762\u2013767 (2011).","journal-title":"Proc Natl Acad Sci USA"},{"key":"5993_CR15","doi-asserted-by":"publisher","first-page":"e1004431","DOI":"10.1371\/journal.pgen.1004431","volume":"10","author":"GB Banks","year":"2014","unstructured":"Banks, G. B., Combs, A. C., Odom, G. L., Bloch, R. J. & Chamberlain, J. S. Muscle structure influences utrophin expression in mdx mice. PLoS Genet \n                           10, e1004431 (2014).","journal-title":"PLoS Genet"},{"key":"5993_CR16","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1073\/pnas.81.4.1189","volume":"81","author":"G Bulfield","year":"1984","unstructured":"Bulfield, G., Siller, W. G., Wight, P. A. & Moore, K. J. X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci USA \n                           81, 1189\u20131192 (1984).","journal-title":"Proc Natl Acad Sci USA"},{"key":"5993_CR17","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1093\/hmg\/ddl083","volume":"15","author":"KA Kleopa","year":"2006","unstructured":"Kleopa, K. A., Drousiotou, A., Mavrikiou, E., Ormiston, A. & Kyriakides, T. Naturally occurring utrophin correlates with disease severity in Duchenne muscular dystrophy. Hum Mol Genet \n                           15, 1623\u20131628 (2006).","journal-title":"Hum Mol Genet"},{"key":"5993_CR18","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1242\/jcs.01584","volume":"118","author":"EO Hernandez-Gonzalez","year":"2005","unstructured":"Hernandez-Gonzalez, E. O., Mornet, D., Rendon, A. & Martinez-Rojas, D. Absence of Dp71 in mdx3cv mouse spermatozoa alters flagellar morphology and the distribution of ion channels and nNOS. J Cell Sci \n                           118, 137\u2013145 (2005).","journal-title":"J Cell Sci"},{"key":"5993_CR19","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1016\/S0092-8674(00)80532-2","volume":"90","author":"AE Deconinck","year":"1997","unstructured":"Deconinck, A. E. et al. Utrophin-dystrophin-deficient mice as a model for Duchenne muscular dystrophy. Cell \n                           90, 717\u2013727 (1997).","journal-title":"Cell"},{"key":"5993_CR20","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1016\/S0092-8674(00)80533-4","volume":"90","author":"RM Grady","year":"1997","unstructured":"Grady, R. M. et al. Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy. Cell \n                           90, 729\u2013738 (1997).","journal-title":"Cell"},{"key":"5993_CR21","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1007\/978-1-60761-103-5_16","volume":"558","author":"EA Ahmed","year":"2009","unstructured":"Ahmed, E. A. & de Rooij, D. G. Staging of mouse seminiferous tubule cross-sections. Methods Mol Biol \n                           558, 263\u2013277 (2009).","journal-title":"Methods Mol Biol"},{"key":"5993_CR22","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1007\/978-1-62703-038-0_27","volume":"927","author":"ML Meistrich","year":"2013","unstructured":"Meistrich, M. L. & Hess, R. A. Assessment of spermatogenesis through staging of seminiferous tubules. Methods Mol Biol \n                           927, 299\u2013307 (2013).","journal-title":"Methods Mol Biol"},{"key":"5993_CR23","doi-asserted-by":"publisher","first-page":"40S","DOI":"10.1177\/0192623312454337","volume":"40","author":"D Creasy","year":"2012","unstructured":"Creasy, D. et al. Proliferative and nonproliferative lesions of the rat and mouse male reproductive system. Toxicol Pathol \n                           40, 40S\u2013121S (2012).","journal-title":"Toxicol Pathol"},{"key":"5993_CR24","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.ydbio.2012.10.006","volume":"373","author":"KR Schwab","year":"2013","unstructured":"Schwab, K. R., Smith, G. D. & Dressler, G. R. Arrested spermatogenesis and evidence for DNA damage in PTIP mutant testes. Dev Biol \n                           373, 64\u201371 (2013).","journal-title":"Dev Biol"},{"key":"5993_CR25","doi-asserted-by":"publisher","first-page":"4394","DOI":"10.1093\/hmg\/dds272","volume":"21","author":"PS Tanwar","year":"2012","unstructured":"Tanwar, P. S., Kaneko-Tarui, T., Zhang, L. & Teixeira, J. M. Altered LKB1\/AMPK\/TSC1\/TSC2\/mTOR signaling causes disruption of Sertoli cell polarity and spermatogenesis. Hum Mol Genet \n                           21, 4394\u20134405 (2012).","journal-title":"Hum Mol Genet"},{"key":"5993_CR26","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1101\/gad.14.11.1332","volume":"14","author":"M Komada","year":"2000","unstructured":"Komada, M., McLean, D. J., Griswold, M. D., Russell, L. D. & Soriano, P. E-MAP-115, encoding a microtubule-associated protein, is a retinoic acid-inducible gene required for spermatogenesis. Genes Dev \n                           14, 1332\u20131342 (2000).","journal-title":"Genes Dev"},{"key":"5993_CR27","doi-asserted-by":"publisher","first-page":"3333","DOI":"10.1093\/hmg\/11.26.3333","volume":"11","author":"S Squire","year":"2002","unstructured":"Squire, S. et al. Prevention of pathology in mdx mice by expression of utrophin: analysis using an inducible transgenic expression system. Hum Mol Genet \n                           11, 3333\u20133344 (2002).","journal-title":"Hum Mol Genet"},{"key":"5993_CR28","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1038\/nm1197-1216","volume":"3","author":"N Deconinck","year":"1997","unstructured":"Deconinck, N. et al. Expression of truncated utrophin leads to major functional improvements in dystrophin-deficient muscles of mice. Nat Med \n                           3, 1216\u20131221 (1997).","journal-title":"Nat Med"},{"key":"5993_CR29","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1038\/384349a0","volume":"384","author":"JM Tinsley","year":"1996","unstructured":"Tinsley, J. M. et al. Amelioration of the dystrophic phenotype of mdx mice using a truncated utrophin transgene. Nature \n                           384, 349\u2013353 (1996).","journal-title":"Nature"},{"key":"5993_CR30","doi-asserted-by":"publisher","first-page":"7822","DOI":"10.1073\/pnas.0812007106","volume":"106","author":"E Prochniewicz","year":"2009","unstructured":"Prochniewicz, E., Henderson, D., Ervasti, J. M. & Thomas, D. D. Dystrophin and utrophin have distinct effects on the structural dynamics of actin. Proc Natl Acad Sci USA \n                           106, 7822\u20137827 (2009).","journal-title":"Proc Natl Acad Sci USA"},{"key":"5993_CR31","doi-asserted-by":"publisher","first-page":"5723","DOI":"10.1073\/pnas.1323842111","volume":"111","author":"JJ Belanto","year":"2014","unstructured":"Belanto, J. J. et al. Microtubule binding distinguishes dystrophin from utrophin. Proc Natl Acad Sci USA \n                           111, 5723\u20135728 (2014).","journal-title":"Proc Natl Acad Sci USA"},{"key":"5993_CR32","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.cell.2004.12.022","volume":"120","author":"JA Maclean 2nd","year":"2005","unstructured":"Maclean, J. A. 2nd et al. Rhox: a new homeobox gene cluster. Cell \n                           120, 369\u2013382 (2005).","journal-title":"Cell"},{"key":"5993_CR33","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1095\/biolreprod.106.053181","volume":"76","author":"M Tokuda","year":"2007","unstructured":"Tokuda, M., Kadokawa, Y., Kurahashi, H. & Marunouchi, T. CDH1 is a specific marker for undifferentiated spermatogonia in mouse testes. Biol Reprod \n                           76, 130\u2013141 (2007).","journal-title":"Biol Reprod"},{"key":"5993_CR34","doi-asserted-by":"publisher","first-page":"14976","DOI":"10.1073\/pnas.0807297105","volume":"105","author":"EL Anderson","year":"2008","unstructured":"Anderson, E. L. et al. Stra8 and its inducer, retinoic acid, regulate meiotic initiation in both spermatogenesis and oogenesis in mice. Proc Natl Acad Sci USA \n                           105, 14976\u201314980 (2008).","journal-title":"Proc Natl Acad Sci USA"},{"key":"5993_CR35","doi-asserted-by":"publisher","first-page":"4425","DOI":"10.1073\/pnas.72.11.4425","volume":"72","author":"AJ Wyrobek","year":"1975","unstructured":"Wyrobek, A. J. & Bruce, W. R. Chemical induction of sperm abnormalities in mice. Proc Natl Acad Sci USA \n                           72, 4425\u20134429 (1975).","journal-title":"Proc Natl Acad Sci USA"},{"key":"5993_CR36","doi-asserted-by":"publisher","first-page":"261","DOI":"10.4103\/1008-682X.143247","volume":"17","author":"MA Smith","year":"2015","unstructured":"Smith, M. A. et al. Anatase titanium dioxide nanoparticles in mice: evidence for induced structural and functional sperm defects after short-, but not long-, term exposure. Asian J Androl \n                           17, 261\u2013268 (2015).","journal-title":"Asian J Androl"},{"key":"5993_CR37","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1071\/RD04077","volume":"17","author":"YC Yeh","year":"2005","unstructured":"Yeh, Y. C., Yang, V. C., Huang, S. C. & Lo, N. W. Stage-dependent expression of extra-embryonic tissue-spermatogenesis-homeobox gene 1 (ESX1) protein, a candidate marker for X chromosome-bearing sperm. Reprod Fertil Dev \n                           17, 447\u2013455 (2005).","journal-title":"Reprod Fertil Dev"},{"key":"5993_CR38","doi-asserted-by":"publisher","first-page":"13856","DOI":"10.1073\/pnas.0405972101","volume":"101","author":"TO Krag","year":"2004","unstructured":"Krag, T. O. et al. Heregulin ameliorates the dystrophic phenotype in mdx mice. Proc Natl Acad Sci USA \n                           101, 13856\u201313860 (2004).","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05993-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05993-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05993-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T08:08:11Z","timestamp":1671782891000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05993-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,7]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["5993"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-05993-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,7]]},"assertion":[{"value":"10 January 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 June 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 August 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"7372"}}