{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:17:35Z","timestamp":1790702255222,"version":"4.1.0"},"reference-count":46,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2020,1,29]],"date-time":"2020-01-29T00:00:00Z","timestamp":1580256000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,1,29]],"date-time":"2020-01-29T00:00:00Z","timestamp":1580256000000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,1,29]],"date-time":"2020-01-29T00:00:00Z","timestamp":1580256000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR065439"],"award-info":[{"award-number":["R01AR065439"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","award":["Faculty Scholars"],"award-info":[{"award-number":["Faculty Scholars"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL54737"],"award-info":[{"award-number":["R01HL54737"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R00GM105874"],"award-info":[{"award-number":["R00GM105874"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R03HD091634"],"award-info":[{"award-number":["R03HD091634"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>The vertebral column or spine assembles around the notochord rod which contains a core made of large vacuolated cells. Each vacuolated cell possesses a single \ufb02uid-\ufb01lled vacuole, and loss or fragmentation of these vacuoles in zebrafish leads to spine kinking. Here, we identified a mutation in the kinase gene dstyk that causes fragmentation of notochord vacuoles and a severe congenital scoliosis-like phenotype in zebrafish. Live imaging revealed that Dstyk regulates fusion of membranes with the vacuole. We find that localized disruption of notochord vacuoles causes vertebral malformation and curving of the spine axis at those sites. Accordingly, in dstyk mutants the spine curves increasingly over time as vertebral bone formation compresses the notochord asymmetrically, causing vertebral malformations and kinking of the axis. Together, our data show that notochord vacuoles function as a hydrostatic scaffold that guides symmetrical growth of vertebrae and spine formation.<\/jats:p>","DOI":"10.7554\/elife.51221","type":"journal-article","created":{"date-parts":[[2020,1,29]],"date-time":"2020-01-29T08:00:19Z","timestamp":1580284819000},"source":"Crossref","is-referenced-by-count":65,"title":["Notochord vacuoles absorb compressive bone growth during zebrafish spine formation"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8873-0897","authenticated-orcid":true,"given":"Jennifer","family":"Bagwell","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Duke University, Durham, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Norman","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Duke University, Durham, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Ellis","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Duke University, Durham, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna","family":"Peskin","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Duke University, Durham, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Duke University, Durham, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Biophysics, University of California, San Francisco, San Francisco, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2641-3984","authenticated-orcid":true,"given":"Stacy V","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Biology Department, Boston College, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1154-5810","authenticated-orcid":true,"given":"Sarah K","family":"McMenamin","sequence":"additional","affiliation":[{"name":"Biology Department, Boston College, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0382-0026","authenticated-orcid":true,"given":"Didier YR","family":"Stainier","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Biophysics, University of California, San Francisco, San Francisco, United States"},{"name":"Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3829-0168","authenticated-orcid":true,"given":"Michel","family":"Bagnat","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Duke University, Durham, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2020,1,29]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"1840","DOI":"10.1016\/j.cub.2010.09.012","article-title":"Cse1l is a negative regulator of CFTR-dependent fluid secretion","volume":"20","author":"Bagnat","year":"2010","journal-title":"Current Biology"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1242\/jcs.107805","article-title":"CORVET and HOPS tethering complexes - coordinators of endosome and lysosome fusion","volume":"126","author":"Balderhaar","year":"2013","journal-title":"Journal of Cell Science"},{"key":"bib3","doi-asserted-by":"publisher","DOI":"10.1186\/s12861-016-0102-4","article-title":"Revisiting in vivo staining with alizarin red S--a valuable approach to analyse zebrafish skeletal mineralization during development and regeneration","volume":"16","author":"Bensimon-Brito","year":"2016","journal-title":"BMC Developmental Biology"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.tig.2017.01.001","article-title":"Understanding idiopathic scoliosis: a new zebrafish school of thought","volume":"33","author":"Boswell","year":"2017","journal-title":"Trends in Genetics"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"3953","DOI":"10.1002\/dvdy.21805","article-title":"Identification of nucleus pulposus precursor cells and notochordal remnants in the mouse: implications for disk degeneration and chordoma formation","volume":"237","author":"Choi","year":"2008","journal-title":"Developmental Dynamics"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"9484","DOI":"10.1073\/pnas.1007566108","article-title":"Hedgehog signaling is required for formation of the notochord sheath and patterning of nuclei pulposi within the intervertebral discs","volume":"108","author":"Choi","year":"2011","journal-title":"PNAS"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"14972","DOI":"10.1073\/pnas.1220884110","article-title":"Anion translocation through an Slc26 transporter mediates lumen expansion during tubulogenesis","volume":"110","author":"Deng","year":"2013","journal-title":"PNAS"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1083\/jcb.201212095","article-title":"Notochord vacuoles are lysosome-related organelles that function in Axis and spine morphogenesis","volume":"200","author":"Ellis","year":"2013","journal-title":"The Journal of Cell Biology"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"64","DOI":"10.4161\/bioa.25503","article-title":"The vacuole within: how cellular organization dictates notochord function","volume":"3","author":"Ellis","year":"2013","journal-title":"Bioarchitecture"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"2413","DOI":"10.1016\/j.celrep.2017.05.076","article-title":"A tonoplast P3B-ATPase Mediates Fusion of Two Types of Vacuoles in Petal Cells","volume":"19","author":"Faraco","year":"2017","journal-title":"Cell Reports"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"1733","DOI":"10.1242\/dev.118950","article-title":"Building the backbone: the development and evolution of vertebral patterning","volume":"142","author":"Fleming","year":"2015","journal-title":"Development"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"1982","DOI":"10.1016\/j.cub.2017.05.035","article-title":"Sheath cell invasion and Trans-differentiation repair mechanical damage caused by loss of caveolae in the zebrafish notochord","volume":"27","author":"Garcia","year":"2017","journal-title":"Current Biology"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1111\/j.1749-6632.2008.03452.x","article-title":"Progress in the understanding of the genetic etiology of vertebral segmentation disorders in humans","volume":"1151","author":"Giampietro","year":"2009","journal-title":"Annals of the New York Academy of Sciences"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.ydbio.2013.11.028","article-title":"Loss of col8a1a function during zebrafish embryogenesis results in congenital vertebral malformations","volume":"386","author":"Gray","year":"2014","journal-title":"Developmental Biology"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1126\/science.aaf6419","article-title":"Zebrafish models of idiopathic scoliosis link cerebrospinal fluid flow defects to spine curvature","volume":"352","author":"Grimes","year":"2016","journal-title":"Science"},{"key":"bib16","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06705-0","article-title":"A missense variant in SLC39A8 is associated with severe idiopathic scoliosis","volume":"9","author":"Haller","year":"2018","journal-title":"Nature Communications"},{"key":"bib17","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.37288","article-title":"Patterning the spine","volume":"7","author":"Harris","year":"2018","journal-title":"eLife"},{"key":"bib18","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5777","article-title":"ptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated wnt signalling in disease","volume":"5","author":"Hayes","year":"2014","journal-title":"Nature Communications"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"2901","DOI":"10.1681\/ASN.2017010043","article-title":"Targeted Exome Sequencing Identifies PBX1 as Involved in Monogenic Congenital Anomalies of the Kidney and Urinary Tract","volume":"28","author":"Heidet","year":"2017","journal-title":"Journal of the American Society of Nephrology"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"21372","DOI":"10.1073\/pnas.1214231110","article-title":"Entpd5 is essential for skeletal mineralization and regulates phosphate homeostasis in zebrafish","volume":"109","author":"Huitema","year":"2012","journal-title":"PNAS"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"4365","DOI":"10.1093\/hmg\/ddv170","article-title":"Gpr126\/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice","volume":"24","author":"Karner","year":"2015","journal-title":"Human Molecular Genetics"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1111\/joa.12679","article-title":"The notochord in Atlantic Salmon (Salmo salar L.) undergoes profound morphological and mechanical changes during development","volume":"231","author":"Kryvi","year":"2017","journal-title":"Journal of Anatomy"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"3775","DOI":"10.1242\/dev.021238","article-title":"Restriction of retinoic acid activity by Cyp26b1 is required for proper timing and patterning of osteogenesis during zebrafish development","volume":"135","author":"Laue","year":"2008","journal-title":"Development"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/j.ajhg.2017.01.014","article-title":"Large intragenic deletion in DSTYK underlies Autosomal-Recessive complicated spastic paraparesis, SPG23","volume":"100","author":"Lee","year":"2017","journal-title":"American Journal of Human Genetics"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1101\/gr.135541.111","article-title":"Mutation mapping and identification by whole-genome sequencing","volume":"22","author":"Leshchiner","year":"2012","journal-title":"Genome Research"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"1968","DOI":"10.1016\/j.cub.2017.05.067","article-title":"Caveolae protect notochord cells against catastrophic mechanical failure during development","volume":"27","author":"Lim","year":"2017","journal-title":"Current Biology"},{"key":"bib27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006564","article-title":"Stat3\/Cdc25a-dependent cell proliferation promotes embryonic Axis extension during zebrafish gastrulation","volume":"13","author":"Liu","year":"2017","journal-title":"PLOS Genetics"},{"key":"bib28","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.33843","article-title":"Segmentation of the zebrafish axial skeleton relies on notochord sheath cells and not on the segmentation clock","volume":"7","author":"Lleras Forero","year":"2018","journal-title":"eLife"},{"key":"bib29","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.30657","article-title":"Wilms tumor 1b defines a wound-specific sheath cell subpopulation associated with notochord repair","volume":"7","author":"Lopez-Baez","year":"2018","journal-title":"eLife"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.gde.2006.06.004","article-title":"Cellular morphogenesis in ascidians: how to shape a simple tadpole","volume":"16","author":"Munro","year":"2006","journal-title":"Current Opinion in Genetics & Development"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.gde.2015.01.010","article-title":"Developing pressures: fluid forces driving morphogenesis","volume":"32","author":"Navis","year":"2015","journal-title":"Current Opinion in Genetics & Development"},{"key":"bib32","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2017.0320","article-title":"Tissue self-organization underlies morphogenesis of the notochord","volume":"373","author":"Norman","year":"2018","journal-title":"Philosophical Transactions of the Royal Society B: Biological Sciences"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"2975","DOI":"10.1002\/dvdy.22113","article-title":"Normal table of postembryonic zebrafish development: staging by externally visible anatomy of the living fish","volume":"238","author":"Parichy","year":"2009","journal-title":"Developmental Dynamics"},{"key":"bib34","doi-asserted-by":"publisher","DOI":"10.1242\/dev.159418","article-title":"Direct activation of chordoblasts by retinoic acid is required for segmented centra mineralization during zebrafish spine development","volume":"145","author":"Pogoda","year":"2018","journal-title":"Development"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.ydbio.2013.05.030","article-title":"A col10a1:nlGFP transgenic line displays putative osteoblast precursors at the medaka notochordal sheath prior to mineralization","volume":"381","author":"Renn","year":"2013","journal-title":"Developmental Biology"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"4445","DOI":"10.1242\/dev.101170","article-title":"Rapid identification of kidney cyst mutations by whole exome sequencing in zebrafish","volume":"140","author":"Ryan","year":"2013","journal-title":"Development"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1056\/NEJMoa1214479","article-title":"Mutations in DSTYK and dominant urinary tract malformations","volume":"369","author":"Sanna-Cherchi","year":"2013","journal-title":"The New England Journal of Medicine"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1016\/j.devcel.2012.03.006","article-title":"Regeneration of amputated zebrafish fin rays from de novo osteoblasts","volume":"22","author":"Singh","year":"2012","journal-title":"Developmental Cell"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.cell.2012.02.054","article-title":"A mechanism for gene-environment interaction in the etiology of congenital scoliosis","volume":"149","author":"Sparrow","year":"2012","journal-title":"Cell"},{"key":"bib40","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":"bib41","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06225-x","article-title":"Pkd2l1 is required for mechanoception in cerebrospinal fluid-contacting neurons and maintenance of spine curvature","volume":"9","author":"Sternberg","year":"2018","journal-title":"Nature Communications"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1111\/joa.12067","article-title":"Mineralization of the vertebral bodies in Atlantic Salmon (Salmo salar L.) is initiated segmentally in the form of hydroxyapatite crystal accretions in the notochord sheath","volume":"223","author":"Wang","year":"2013","journal-title":"Journal of Anatomy"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.ydbio.2018.04.005","article-title":"The role of the notochord in amniote vertebral column segmentation","volume":"439","author":"Ward","year":"2018","journal-title":"Developmental Biology"},{"key":"bib44","volume-title":"The Zebrafish Book: A Guide for the Laboratory Use of Zebrafish","author":"Westerfield","year":"2000"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"2026","DOI":"10.1016\/j.celrep.2018.01.084","article-title":"Spine patterning is guided by segmentation of the notochord sheath","volume":"22","author":"Wopat","year":"2018","journal-title":"Cell Reports"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"2527","DOI":"10.1242\/dev.051011","article-title":"Mib-Jag1-Notch signalling regulates patterning and structural roles of the notochord by controlling cell-fate decisions","volume":"137","author":"Yamamoto","year":"2010","journal-title":"Development"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/51221\/elife-51221-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/51221\/elife-51221-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/51221","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T20:57:16Z","timestamp":1697057836000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/51221"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,29]]},"references-count":46,"alternative-id":["10.7554\/eLife.51221"],"URL":"https:\/\/doi.org\/10.7554\/elife.51221","archive":["CLOCKSS"],"relation":{"is-supplemented-by":[{"id-type":"doi","id":"10.5061\/dryad.73n5tb2tb","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.51221.sa1","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.51221.sa2","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,29]]},"article-number":"e51221"}}