{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T14:34:51Z","timestamp":1776436491629,"version":"3.51.2"},"reference-count":67,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T00:00:00Z","timestamp":1622073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:italic>SHOX<\/jats:italic> deficiency causes a spectrum of clinical phenotypes related to skeletal dysplasia and short stature, including L\u00e9ri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Turner syndrome, and idiopathic short stature. SHOX controls chondrocyte proliferation and differentiation, bone maturation, and cellular growth arrest and apoptosis <jats:italic>via<\/jats:italic> transcriptional regulation of its direct target genes <jats:italic>NPPB<\/jats:italic>, <jats:italic>FGFR3<\/jats:italic>, and <jats:italic>CTGF<\/jats:italic>. However, our understanding of SHOX-related pathways is still incomplete. To elucidate the underlying molecular mechanisms and to better understand the broad phenotypic spectrum of <jats:italic>SHOX<\/jats:italic> deficiency, we aimed to identify novel SHOX targets. We analyzed differentially expressed genes in <jats:italic>SHOX<\/jats:italic>-overexpressing human fibroblasts (NHDF), and confirmed the known SHOX target genes <jats:italic>NPPB<\/jats:italic> and <jats:italic>FGFR<\/jats:italic> among the most strongly regulated genes, together with 143 novel candidates. Altogether, 23 genes were selected for further validation, first by whole-body characterization in developing <jats:italic>shox<\/jats:italic>-deficient zebrafish embryos, followed by tissue-specific expression analysis in three <jats:italic>shox<\/jats:italic>-expressing zebrafish tissues: head (including brain, pharyngeal arches, eye, and olfactory epithelium), heart, and pectoral fins. Most genes were physiologically relevant in the pectoral fins, while only few genes were also significantly regulated in head and heart tissue. Interestingly, multiple <jats:italic>sox<\/jats:italic> family members (<jats:italic>sox5<\/jats:italic>, <jats:italic>sox6<\/jats:italic>, <jats:italic>sox8<\/jats:italic>, and <jats:italic>sox18<\/jats:italic>) were significantly dysregulated in <jats:italic>shox<\/jats:italic>-deficient pectoral fins together with other genes (<jats:italic>nppa<\/jats:italic>, <jats:italic>nppc<\/jats:italic>, <jats:italic>cdkn1a<\/jats:italic>, <jats:italic>cdkn1ca<\/jats:italic>, <jats:italic>cyp26b1<\/jats:italic>, and <jats:italic>cy26c1<\/jats:italic>), highlighting an important role for these genes in <jats:italic>shox<\/jats:italic>-related growth disorders. Network-based analysis integrating data from the Ingenuity pathways revealed that most of these genes act in a common network. Our results provide novel insights into the genetic pathways and molecular events leading to the clinical manifestation of <jats:italic>SHOX<\/jats:italic> deficiency.<\/jats:p>","DOI":"10.3389\/fgene.2021.688808","type":"journal-article","created":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T16:56:44Z","timestamp":1622134604000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification and Tissue-Specific Characterization of Novel SHOX-Regulated Genes in Zebrafish Highlights SOX Family Members Among Other Genes"],"prefix":"10.3389","volume":"12","author":[{"given":"Sandra","family":"Hoffmann","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralph","family":"Roeth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Diebold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasmin","family":"Gogel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Hassel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steffen","family":"Just","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gudrun A.","family":"Rappold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e83104","DOI":"10.1371\/journal.pone.0083104","article-title":"NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development","volume":"9","author":"Aza-Carmona","year":"2014","journal-title":"PLoS One"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.1093\/hmg\/ddr032","article-title":"SHOX interacts with the chondrogenic transcription factors SOX5 and SOX6 to activate the aggrecan enhancer","volume":"20","author":"Aza-Carmona","year":"2011","journal-title":"Hum. 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Chem."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1210\/er.2016-1036","article-title":"A track record on SHOX: from basic research to complex models and therapy","volume":"37","author":"Marchini","year":"2016","journal-title":"Endocr. Rev."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1038\/s41431-018-0148-9","article-title":"Functional missense and splicing variants in the retinoic acid catabolizing enzyme CYP26C1 in idiopathic short stature","volume":"26","author":"Montalbano","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.15252\/emmm.201606623","article-title":"Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency","volume":"8","author":"Montalbano","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s12920-018-0445-8","article-title":"Co-occurrence of genomic imbalances on Xp22.1 in the SHOX region and 15q25.2 in a girl with short stature, precocious puberty, urogenital malformations and bone anomalies","volume":"12","author":"Monzani","year":"2019","journal-title":"BMC Med. 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Chem."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"2927","DOI":"10.1210\/jcem.85.8.6745","article-title":"Short stature homeobox-containing gene duplication on the der(X) chromosome in a female with 45,X\/46,X, der(X), gonadal dysgenesis, and tall stature","volume":"85","author":"Ogata","year":"2000","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.endonu.2011.06.005","article-title":"The role of the SHOX gene in the pathophysiology of Turner syndrome","volume":"58","author":"Oliveira","year":"2011","journal-title":"Endocrinol. Nutr."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1002\/bdra.20709","article-title":"The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis","volume":"88","author":"Pennimpede","year":"2010","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"bav028","DOI":"10.1093\/database\/bav028","article-title":"DisGeNET: a discovery platform for the dynamical exploration of human diseases and their genes","volume":"2015","author":"Pinero","year":"2015","journal-title":"Database"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"4625","DOI":"10.1093\/hmg\/ddq393","article-title":"Shox2 mediates Tbx5 activity by regulating Bmp4 in the pacemaker region of the developing heart","volume":"19","author":"Puskaric","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"3083","DOI":"10.1093\/hmg\/10.26.3083","article-title":"The Leri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activator","volume":"10","author":"Rao","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1038\/ng0597-54","article-title":"Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome","volume":"16","author":"Rao","year":"1997","journal-title":"Nat. Genet."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1534\/genetics.110.118802","article-title":"A genomic imprinting defect in mice traced to a single gene","volume":"186","author":"Rentsendorj","year":"2010","journal-title":"Genetics"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"E1257","DOI":"10.1210\/jc.2011-3460","article-title":"Genotypes and phenotypes of children with SHOX deficiency in France","volume":"97","author":"Rosilio","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1161\/01.RES.0000234807.16034.fe","article-title":"Cardiac myosin light chain-2: a novel essential component of thick-myofilament assembly and contractility of the heart","volume":"99","author":"Rottbauer","year":"2006","journal-title":"Circ. Res."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1002\/dvdy.24239","article-title":"In vivo loss of function study reveals the short stature homeobox-containing (shox) gene plays indispensable roles in early embryonic growth and bone formation in zebrafish","volume":"244","author":"Sawada","year":"2015","journal-title":"Dev. Dyn."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1093\/nar\/28.6.1473","article-title":"Cloning and characterisation of the Sry-related transcription factor gene Sox8","volume":"28","author":"Schepers","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1038\/sj.ejhg.5200402","article-title":"Phenotypic variation and genetic heterogeneity in Leri-Weill syndrome","volume":"8","author":"Schiller","year":"2000","journal-title":"Eur. J. Hum. Genet."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1002\/humu.20187","article-title":"Alteration of DNA binding, dimerization, and nuclear translocation of SHOX homeodomain mutations identified in idiopathic short stature and Leri-Weill dyschondrosteosis","volume":"26","author":"Schneider","year":"2005","journal-title":"Hum. Mutat."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/ng0198-70","article-title":"Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis","volume":"19","author":"Shears","year":"1998","journal-title":"Nat. Genet."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"3765","DOI":"10.1242\/dev.024034","article-title":"Retinoic acid and Cyp26b1 are critical regulators of osteogenesis in the axial skeleton","volume":"135","author":"Spoorendonk","year":"2008","journal-title":"Development"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1038\/386288a0","article-title":"Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism","volume":"386","author":"Su","year":"1997","journal-title":"Nature"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"e66048","DOI":"10.1371\/journal.pone.0066048","article-title":"Genotype-phenotype correlation of 2q37 deletions including NPPC gene associated with skeletal malformations","volume":"8","author":"Tassano","year":"2013","journal-title":"PLoS One"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1086\/508433","article-title":"A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome","volume":"79","author":"Toydemir","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1136\/jmedgenet-2015-103621","article-title":"Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions","volume":"53","author":"Tropeano","year":"2016","journal-title":"J. Med. Genet."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"17667","DOI":"10.1038\/srep17667","article-title":"Profiling of conserved non-coding elements upstream of SHOX and functional characterisation of the SHOX cis-regulatory landscape","volume":"5","author":"Verdin","year":"2015","journal-title":"Sci. Rep."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.ydbio.2010.11.031","article-title":"Shox2 function couples neural, muscular and skeletal development in the proximal forelimb","volume":"350","author":"Vickerman","year":"2011","journal-title":"Dev. Biol."},{"key":"ref63","volume-title":"The Zebrafish Book: A Guide for the Laboratory Use of Zebrafish (","author":"Westerfield","year":"2000"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1101\/gad.11.8.973","article-title":"Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development","volume":"11","author":"Yan","year":"1997","journal-title":"Genes Dev."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"125","DOI":"10.3389\/fendo.2017.00125","article-title":"The short-stature homeobox-containing gene (shox\/SHOX) is required for the regulation of cell proliferation and bone differentiation in zebrafish embryo and human mesenchymal stem cells","volume":"8","author":"Yokokura","year":"2017","journal-title":"Front. 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