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dc.contributor.authorMerkes, Chris M.
dc.contributor.authorTurkalo, Timothy K.
dc.contributor.authorWilder, Nicole
dc.contributor.authorPark, Hyewon
dc.contributor.authorWenger, Luke William
dc.contributor.authorLewin, Seth J.
dc.contributor.authorAzuma, Mizuki
dc.date.accessioned2015-03-05T20:20:40Z
dc.date.available2015-03-05T20:20:40Z
dc.date.issued2015-01-24
dc.identifier.citationMerkes C, Turkalo TK, Wilder N, Park H, Wenger LW, et al. (2015) Ewing Sarcoma Ewsa Protein Regulates Chondrogenesis of Meckel’s Cartilage through Modulation of Sox9 in Zebrafish. PLoS ONE 10(1): e0116627.

http://dx.doi.org/10.1371/journal.pone.0116627
en_US
dc.identifier.urihttp://hdl.handle.net/1808/16974
dc.description.abstractEwing sarcoma is the second most common skeletal (bone and cartilage) cancer in adolescents, and it is characterized by the expression of the aberrant chimeric fusion gene EWS/FLI1. Wild-type EWS has been proposed to play a role in mitosis, splicing and transcription. We have previously shown that EWS/FLI1 interacts with EWS, and it inhibits EWS activity in a dominant manner. Ewing sarcoma is a cancer that specifically develops in skeletal tissues, and although the above data suggests the significance of EWS, its role in chondrogenesis/skeletogenesis is not understood. To elucidate the function of EWS in skeletal development, we generated and analyzed a maternal zygotic (MZ) ewsa/ewsa line because the ewsa/wt and ewsa/ewsa zebrafish appeared to be normal and fertile. Compared with wt/wt, the Meckel’s cartilage of MZ ewsa/ewsa mutants had a higher number of craniofacial prehypertrophic chondrocytes that failed to mature into hypertrophic chondrocytes at 4 days post-fertilization (dpf). Ewsa interacted with Sox9, which is the master transcription factor for chondrogenesis. Sox9 target genes were either upregulated (ctgfa, ctgfb, col2a1a, and col2a1b) or downregulated (sox5, nog1, nog2, and bmp4) in MZ ewsa/ewsa embryos compared with the wt/wt zebrafish embryos. Among these Sox9 target genes, the chromatin immunoprecipitation (ChIP) experiment demonstrated that Ewsa directly binds to ctgfa and ctgfb loci. Consistently, immunohistochemistry showed that the Ctgf protein is upregulated in the Meckel’s cartilage of MZ ewsa/ewsa mutants. Together, we propose that Ewsa promotes the differentiation from prehypertrophic chondrocytes to hypertrophic chondrocytes of Meckel’s cartilage through inhibiting Sox9 binding site of the ctgf gene promoter. Because Ewing sarcoma specifically develops in skeletal tissue that is originating from chondrocytes, this new role of EWS may provide a potential molecular basis of its pathogenesis.en_US
dc.description.sponsorshipThis manuscript was supported by the Massman Family Ewing Sarcoma Research Fund, the Sarcoma Foundation of America, P20RR016475 / P20GM103418 and P20 RR032682-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en_US
dc.publisherPublic Library of Scienceen_US
dc.rights© 2015 Merkes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleEwing Sarcoma Eswa Protein Regulates Chondrogenesis of Meckel's Cartilage through Modulation of Sox9 in Zebrafishen_US
dc.typeArticle
kusw.kuauthorMerkes, Chris M.
kusw.kuauthorWilder, Nicole
kusw.kuauthorPark, Hyewon
kusw.kuauthorWenger, Luke W.
kusw.kuauthorLewin, Seth J.
kusw.kuauthorAzuma, Mizuki
kusw.kuauthorTurkalo, Timothy
kusw.kudepartmentDepartment of Molecular Biosciencesen_US
dc.identifier.doi10.1371/journal.pone.0116627
dc.identifier.orcidhttps://orcid.org/0000-0001-8191-627X
kusw.oaversionScholarly/refereed, publisher version
kusw.oapolicyThis item meets KU Open Access policy criteria.
dc.rights.accessrightsopenAccess


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© 2015 Merkes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Except where otherwise noted, this item's license is described as: © 2015 Merkes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited