Identification of vertebra-like elements and their possible differentiation from sclerotomes in the hagfish

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However, it has yet to be conclusively shown whether hagfish lack all vertebra-like structures, and whether their somites follow developmental processes and patterning distinct from those in lampreys and gnathostomes. Here we report the presence of vertebra-like cartilages in the in-shore hagfish, Eptatretus burgeri. These elements arise as small nodules occupying anatomical positions comparable to those of gnathostome vertebrae. Examination of hagfish embryos suggests that the ventromedial portion of a somite transforms into mesenchymal cells that express cognates of Pax1/9 and Twist, strikingly similar to the pattern of sclerotome development in gnathostomes. We conclude that the vertebra-like elements in the hagfish are homologous to gnathostome vertebrae, implying that this animal underwent secondary reduction of vertebrae in most of the trunk. Hagfish, a group of extant jawless fish, lack true vertebrae, but it is not clear if hagfish lack all vertebrata-like structures. 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data-test="article-identifier"> <li class="c-article-identifiers__item" data-test="article-category">Article</li> <li class="c-article-identifiers__item"> <a href="https://www.springernature.com/gp/open-research/about/the-fundamentals-of-open-access-and-open-research" data-track="click" data-track-action="open access" data-track-label="link" class="u-color-open-access" data-test="open-access">Open access</a> </li> <li class="c-article-identifiers__item">Published: <time datetime="2011-06-28">28 June 2011</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title="">Identification of vertebra-like elements and their possible differentiation from sclerotomes in the hagfish</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Kinya_G_-Ota-Aff1-Aff2" data-author-popup="auth-Kinya_G_-Ota-Aff1-Aff2" data-author-search="Ota, Kinya G." data-corresp-id="c1">Kinya G. Ota<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Satoko-Fujimoto-Aff1" data-author-popup="auth-Satoko-Fujimoto-Aff1" data-author-search="Fujimoto, Satoko">Satoko Fujimoto</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Yasuhiro-Oisi-Aff1" data-author-popup="auth-Yasuhiro-Oisi-Aff1" data-author-search="Oisi, Yasuhiro">Yasuhiro Oisi</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 4 authors for this article" title="Show all 4 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Shigeru-Kuratani-Aff1" data-author-popup="auth-Shigeru-Kuratani-Aff1" data-author-search="Kuratani, Shigeru">Shigeru Kuratani</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/ncomms" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Nature Communications</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 2</b>, Article number: <span data-test="article-number">373</span> (<span data-test="article-publication-year">2011</span>) <a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">9230 <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p class="c-article-metrics-bar__count">72 <span class="c-article-metrics-bar__label">Citations</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">36 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/ncomms1355/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> <div class="u-js-hide" data-component="article-subject-links"> <h3 class="c-article__sub-heading">Subjects</h3> <ul class="c-article-subject-list"> <li class="c-article-subject-list__subject"><a href="/subjects/differentiation" data-track="click" data-track-action="view subject" data-track-label="link">Differentiation</a></li><li class="c-article-subject-list__subject"><a href="/subjects/embryogenesis" data-track="click" data-track-action="view subject" data-track-label="link">Embryogenesis</a></li><li class="c-article-subject-list__subject"><a href="/subjects/ichthyology" data-track="click" data-track-action="view subject" data-track-label="link">Ichthyology</a></li><li class="c-article-subject-list__subject"><a href="/subjects/pattern-formation" data-track="click" data-track-action="view subject" data-track-label="link">Pattern formation</a></li> </ul> </div> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>The hagfish, a group of extant jawless fish, are known to lack true vertebrae and, for this reason, have often been excluded from the group Vertebrata. However, it has yet to be conclusively shown whether hagfish lack all vertebra-like structures, and whether their somites follow developmental processes and patterning distinct from those in lampreys and gnathostomes. Here we report the presence of vertebra-like cartilages in the in-shore hagfish, <i>Eptatretus burgeri</i>. These elements arise as small nodules occupying anatomical positions comparable to those of gnathostome vertebrae. Examination of hagfish embryos suggests that the ventromedial portion of a somite transforms into mesenchymal cells that express cognates of <i>Pax1/9</i> and <i>Twist</i>, strikingly similar to the pattern of sclerotome development in gnathostomes. We conclude that the vertebra-like elements in the hagfish are homologous to gnathostome vertebrae, implying that this animal underwent secondary reduction of vertebrae in most of the trunk.</p></div></div></section> <noscript> </noscript> <section aria-labelledby="inline-recommendations" data-title="Inline Recommendations" class="c-article-recommendations" data-track-component="inline-recommendations"> <h3 class="c-article-recommendations-title" id="inline-recommendations">Similar content being viewed by others</h3> <div class="c-article-recommendations-list"> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41598-024-54435-9/MediaObjects/41598_2024_54435_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41598-024-54435-9?fromPaywallRec=false" data-track="select_recommendations_1" data-track-context="inline recommendations" data-track-action="click recommendations inline - 1" data-track-label="10.1038/s41598-024-54435-9">Loss of <i>noggin1</i>, a classic embryonic inducer gene, in elasmobranchs </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">15 February 2024</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41598-021-82122-6/MediaObjects/41598_2021_82122_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41598-021-82122-6?fromPaywallRec=false" data-track="select_recommendations_2" data-track-context="inline recommendations" data-track-action="click recommendations inline - 2" data-track-label="10.1038/s41598-021-82122-6">Non-collinear Hox gene expression in bivalves and the evolution of morphological novelties in mollusks </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">11 February 2021</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41598-024-70724-9/MediaObjects/41598_2024_70724_Fig1_HTML.jpg" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41598-024-70724-9?fromPaywallRec=false" data-track="select_recommendations_3" data-track-context="inline recommendations" data-track-action="click recommendations inline - 3" data-track-label="10.1038/s41598-024-70724-9">The larval chondrocranium and its development in <i>Smilisca phaeota</i> with considerations of patterns characteristic for the chondrocranial development of Lalagobatrachia </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">26 August 2024</span> </div> </div> </article> </div> </div> </section> <script> window.dataLayer = window.dataLayer || []; window.dataLayer.push({ recommendations: { recommender: 'semantic', model: 'specter', policy_id: 'NA', timestamp: 1732475177, embedded_user: 'null' } }); </script> <div class="main-content"> <section data-title="Introduction"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Introduction</h2><div class="c-article-section__content" id="Sec1-content"><p>Vertebrae arise as segmental endoskeletal elements associated with the notochord, and are regarded as a vertebrate synapomorphy<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Janvier, P. Early Vertebrates (Oxford University Press, 1996)." href="/articles/ncomms1355#ref-CR1" id="ref-link-section-d228159420e375">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Kardong, K. V. Vertebrates Comparative Anatomy, Function, Evolution (McGraw-Hill Higher Education, 2008)." href="/articles/ncomms1355#ref-CR2" id="ref-link-section-d228159420e378">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Goodrich, E. S. Vertebrata Craniata. (First Fascicle; Cyclostomes and Fishes) (Adam and Charles Black, 1909)." href="/articles/ncomms1355#ref-CR3" id="ref-link-section-d228159420e381">3</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Goodrich, E. S. Studies on the Structure and Development of Vertebrates (McMillan, 1930)." href="/articles/ncomms1355#ref-CR4" id="ref-link-section-d228159420e384">4</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Kent, G. C. & Carr, R. K. Comparative Anatomy of the Vertebrates (McGraw-Hill, 2001)." href="/articles/ncomms1355#ref-CR5" id="ref-link-section-d228159420e387">5</a></sup>. No such structures, nor the somite-derived vertebral primordial, the sclerotome, are present in non-vertebrate chordates such as amphioxus and the tunicates<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Shimeld, S. M. & Holland, P. W. H. Vertebrate innovations. Proc. Natl Acad. Sci. USA 97, 4449–4452 (2000)." href="/articles/ncomms1355#ref-CR6" id="ref-link-section-d228159420e391">6</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Scaal, M. & Wiegreffe, C. Somite compartments in anamniotes. Anat. Embryol. 211 (Suppl 1), 9–19 (2006)." href="/articles/ncomms1355#ref-CR7" id="ref-link-section-d228159420e394">7</a></sup>. The vertebrae in gnathostomes, the jawed vertebrates, consist of dorsal and ventral elements<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Janvier, P. Early Vertebrates (Oxford University Press, 1996)." href="/articles/ncomms1355#ref-CR1" id="ref-link-section-d228159420e398">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Kardong, K. V. Vertebrates Comparative Anatomy, Function, Evolution (McGraw-Hill Higher Education, 2008)." href="/articles/ncomms1355#ref-CR2" id="ref-link-section-d228159420e401">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Goodrich, E. S. Vertebrata Craniata. (First Fascicle; Cyclostomes and Fishes) (Adam and Charles Black, 1909)." href="/articles/ncomms1355#ref-CR3" id="ref-link-section-d228159420e404">3</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Goodrich, E. S. Studies on the Structure and Development of Vertebrates (McMillan, 1930)." href="/articles/ncomms1355#ref-CR4" id="ref-link-section-d228159420e407">4</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Kent, G. C. & Carr, R. K. Comparative Anatomy of the Vertebrates (McGraw-Hill, 2001)." href="/articles/ncomms1355#ref-CR5" id="ref-link-section-d228159420e410">5</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Miles, R. S. Remarks on the vertebral column and caudal fin of acanthodian fishes. Lethaia 3, 343–362 (1970)." href="/articles/ncomms1355#ref-CR8" id="ref-link-section-d228159420e413">8</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Dennis, K. & Miles, R. S. A pachyosteomorph arthrodire from Gogo, Western Australia. Zool. J. Linn. Soc. 73, 213–258 (1981)." href="/articles/ncomms1355#ref-CR9" id="ref-link-section-d228159420e417">9</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Coates, M. I. & Sequeira, S. E. K. A new stethacanthid chondrichthyan from the lower Carboniferous of Bearsden, Scotand. J. Vert. Paleontol. 21, 438–459 (2001)." href="/articles/ncomms1355#ref-CR10" id="ref-link-section-d228159420e420">10</a></sup>, of which only the dorsal elements are present in lampreys<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Tretjakoff, D. Die Wirbeläule des Neunauges. Anat. Anz. 61, 387–396 (1926)." href="/articles/ncomms1355#ref-CR11" id="ref-link-section-d228159420e424">11</a></sup>, one of the two extant agnathan taxa (jawless fishes)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Janvier, P. Early Vertebrates (Oxford University Press, 1996)." href="/articles/ncomms1355#ref-CR1" id="ref-link-section-d228159420e428">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Kardong, K. V. Vertebrates Comparative Anatomy, Function, Evolution (McGraw-Hill Higher Education, 2008)." href="/articles/ncomms1355#ref-CR2" id="ref-link-section-d228159420e431">2</a></sup>. Based on evidence that the vertebrae of the gnathostomes and lampreys are developmentally derived from the sclerotome<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Christ, B., Huang, R. & Scaal, M. Formation and differentiation of the avian sclerotome. Anat. Embryol. 208, 333–350 (2004)." href="/articles/ncomms1355#ref-CR12" id="ref-link-section-d228159420e436">12</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Zhang, G., Miyamoto, M. M. & Cohn, M. J. Lamprey type II collagen and Sox9 reveal an ancient origin of the vertebrate collagenous skeleton. Proc. Natl Acad. Sci. USA 103, 3180–3185 (2006)." href="/articles/ncomms1355#ref-CR13" id="ref-link-section-d228159420e439">13</a></sup>, it is thought that their developmental mechanisms share the same ancestral origin. However, another extant agnathan, the hagfish, has generally been thought to lack vertebrae; the axial supporting tissue of this animal has been described as consisting only of notochord and cartilaginous fin rays<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Janvier, P. Early Vertebrates (Oxford University Press, 1996)." href="/articles/ncomms1355#ref-CR1" id="ref-link-section-d228159420e443">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Kardong, K. V. Vertebrates Comparative Anatomy, Function, Evolution (McGraw-Hill Higher Education, 2008)." href="/articles/ncomms1355#ref-CR2" id="ref-link-section-d228159420e446">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Goodrich, E. S. Vertebrata Craniata. (First Fascicle; Cyclostomes and Fishes) (Adam and Charles Black, 1909)." href="/articles/ncomms1355#ref-CR3" id="ref-link-section-d228159420e449">3</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Goodrich, E. S. Studies on the Structure and Development of Vertebrates (McMillan, 1930)." href="/articles/ncomms1355#ref-CR4" id="ref-link-section-d228159420e452">4</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Müller, J. Vergleichende Anatomie der Myxinoiden (Akademie der Wissenschaften, 1834)." href="/articles/ncomms1355#ref-CR14" id="ref-link-section-d228159420e455">14</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Parker, K. W. On the skeleton of the marsipobranch fishes. Part I. The Myxinoids (Myxine, and Bdellostoma). Philos. Trans. R. Soc. Lond. 174, 373–409 (1883)." href="/articles/ncomms1355#ref-CR15" id="ref-link-section-d228159420e458">15</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Cole, F. J. A monograph on the general morphology of myxinoid fishes, based on a study of Myxine. Part 1. The anatomy of the skeleton. Trans. R. Soc. Edinb. 41, 749–788 (1905)." href="/articles/ncomms1355#ref-CR16" id="ref-link-section-d228159420e462">16</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Marinelli, W. & Strenger, A. Vergleichende Anatomie und Morphologie der Wirbeltiere. 2. Myxine Glutinosa (L.) (Franz Deuticke, 1956)." href="/articles/ncomms1355#ref-CR17" id="ref-link-section-d228159420e465">17</a></sup>. Because of this morphological trait, the hagfish was excluded from the Vertebrata in some textbooks<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Janvier, P. Early Vertebrates (Oxford University Press, 1996)." href="/articles/ncomms1355#ref-CR1" id="ref-link-section-d228159420e469">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Kardong, K. V. Vertebrates Comparative Anatomy, Function, Evolution (McGraw-Hill Higher Education, 2008)." href="/articles/ncomms1355#ref-CR2" id="ref-link-section-d228159420e472">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Kent, G. C. & Carr, R. K. Comparative Anatomy of the Vertebrates (McGraw-Hill, 2001)." href="/articles/ncomms1355#ref-CR5" id="ref-link-section-d228159420e475">5</a></sup>, although its vertebrate affinities, as observed in the brain and skull, are widely recognized<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Janvier, P. Early Vertebrates (Oxford University Press, 1996)." href="/articles/ncomms1355#ref-CR1" id="ref-link-section-d228159420e479">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Kardong, K. V. Vertebrates Comparative Anatomy, Function, Evolution (McGraw-Hill Higher Education, 2008)." href="/articles/ncomms1355#ref-CR2" id="ref-link-section-d228159420e482">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Goodrich, E. S. Vertebrata Craniata. (First Fascicle; Cyclostomes and Fishes) (Adam and Charles Black, 1909)." href="/articles/ncomms1355#ref-CR3" id="ref-link-section-d228159420e485">3</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Goodrich, E. S. Studies on the Structure and Development of Vertebrates (McMillan, 1930)." href="/articles/ncomms1355#ref-CR4" id="ref-link-section-d228159420e488">4</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Kent, G. C. & Carr, R. K. Comparative Anatomy of the Vertebrates (McGraw-Hill, 2001)." href="/articles/ncomms1355#ref-CR5" id="ref-link-section-d228159420e491">5</a></sup>. This raises a number of questions; specifically, whether the hagfish truly lacks any form of vertebra-like structure throughout its body and life cycle, and whether hagfish somites in the embryonic trunk are dissimilar to those in lampreys and gnathostomes. Importantly, one of the early reports on hagfish anatomy, in fact, described segmental cartilaginous elements (putative vertebral elements) on the ventral aspect of the caudal notochord in <i>Bdellostoma</i> more than a century ago (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/ncomms1355#MOESM344">Supplementary Fig. S1</a>)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Ayers, H. & Jackson, C. M. Morphology of the myxinoidei. I. Skeleton and musculature. J. Morphol. 17, 185–226 (1900)." href="/articles/ncomms1355#ref-CR18" id="ref-link-section-d228159420e502">18</a></sup>. These cartilaginous structures have not been re-examined, and have largely been overlooked by subsequent researchers<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Cole, F. J. A monograph on the general morphology of myxinoid fishes, based on a study of Myxine. Part 1. The anatomy of the skeleton. Trans. R. Soc. Edinb. 41, 749–788 (1905)." href="/articles/ncomms1355#ref-CR16" id="ref-link-section-d228159420e506">16</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Marinelli, W. & Strenger, A. Vergleichende Anatomie und Morphologie der Wirbeltiere. 2. Myxine Glutinosa (L.) (Franz Deuticke, 1956)." href="/articles/ncomms1355#ref-CR17" id="ref-link-section-d228159420e509">17</a></sup>.</p><p>To address these questions, we conducted detailed anatomical and histological analyses on the in-shore Japanese hagfish, <i>Eptatretus burgeri</i>, and discovered putative vertebral elements in the caudalmost region of the body axis. These skeletal elements are small cartilaginous nodules mostly located on the ventral aspect of the notochord, reminiscent of the gnathostome hemal arch, which, if not segmented, are in register with myomeres. Furthermore, we obtained a series of early- to late-stage hagfish embryos. Their examination suggests that the ventromedial portions of somites transform into mesenchymal cell masses that express cognates of <i>Pax1/9</i> and <i>Twist</i>, similar to vertebral primodia in gnathostomes<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Christ, B., Huang, R. & Scaal, M. Formation and differentiation of the avian sclerotome. Anat. Embryol. 208, 333–350 (2004)." href="/articles/ncomms1355#ref-CR12" id="ref-link-section-d228159420e525">12</a></sup>. On the basis of these observations, we propose that the apparent lack of vertebrae in the hagfish stems from secondary developmental suppression of the vertebral differentiation programme for most of the trunk somites.</p></div></div></section><section data-title="Results"><div class="c-article-section" id="Sec2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec2">Results</h2><div class="c-article-section__content" id="Sec2-content"><h3 class="c-article__sub-heading" id="Sec3">The adult skeletal morphology</h3><p>In adult specimens of <i>E. burgeri</i>, we found putative vertebral elements in the post-cloacal axis (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig1">Fig. 1a–e</a>)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Ayers, H. & Jackson, C. M. Morphology of the myxinoidei. I. Skeleton and musculature. J. Morphol. 17, 185–226 (1900)." href="/articles/ncomms1355#ref-CR18" id="ref-link-section-d228159420e547">18</a></sup>. Histochemical observation indicated that these structures were cartilaginous nodules; the chondrocytes in each nodule were separated by a thin layer of extracellular matrices that were stained with Alcian blue, which detects mucopolysaccharides, as in gnathostomes (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig1">Figs 1c–e</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig2">2a,b</a>)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Kardong, K. V. Vertebrates Comparative Anatomy, Function, Evolution (McGraw-Hill Higher Education, 2008)." href="/articles/ncomms1355#ref-CR2" id="ref-link-section-d228159420e558">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Hall, B. K. Bones and Cartilage: Development and Evolutionary Skeletal Biology (Elsevier, 2005)." href="/articles/ncomms1355#ref-CR19" id="ref-link-section-d228159420e561">19</a></sup>. These cartilages consisted of a pair of elements on both sides of the dorsal aorta, a single median element beneath the aorta, and another pair adhering to the ventral aspect of the notochordal sheath (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig1">Fig. 1c,d</a>). The distribution of these nodules was restricted to a part of the post-cloacal region that roughly corresponded to the position between the 80th and 100th myomeres and was dorsal to the mucus glands (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig1">Fig. 1a,b</a>). Unlike the vertebrae of lampreys and gnathostomes (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig2">Fig. 2c–f</a>), these cartilages did not show a clear segmental pattern in register with myomeres. The overall morphology of these elements was reminiscent of hemal arches in gnathostomes (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig1">Figs 1c</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig2">2a,e</a>)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Janvier, P. Early Vertebrates (Oxford University Press, 1996)." href="/articles/ncomms1355#ref-CR1" id="ref-link-section-d228159420e581">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Kardong, K. V. Vertebrates Comparative Anatomy, Function, Evolution (McGraw-Hill Higher Education, 2008)." href="/articles/ncomms1355#ref-CR2" id="ref-link-section-d228159420e584">2</a></sup>. On the dorsal side of the notochord at the same axial level, the median plate-like cartilaginous element was associated with dorsal fin rays, which were also present at the post-cloacal level of the trunk. This cartilage was previously designated as the 'median dorsal bar'<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Ayers, H. & Jackson, C. M. Morphology of the myxinoidei. I. Skeleton and musculature. J. Morphol. 17, 185–226 (1900)." href="/articles/ncomms1355#ref-CR18" id="ref-link-section-d228159420e588">18</a></sup>. As seen in the transverse section of the most caudal level, the median dorsal bar was attached to a pair of cartilaginous arches on both sides of the notochord (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig1">Fig. 1e</a>). The anatomical configuration of these cartilages is strikingly reminiscent of the neural spine and the paired neural arches in gnathostomes (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig2">Fig. 2e</a>)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Janvier, P. Early Vertebrates (Oxford University Press, 1996)." href="/articles/ncomms1355#ref-CR1" id="ref-link-section-d228159420e598">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Kardong, K. V. Vertebrates Comparative Anatomy, Function, Evolution (McGraw-Hill Higher Education, 2008)." href="/articles/ncomms1355#ref-CR2" id="ref-link-section-d228159420e601">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Goodrich, E. S. Vertebrata Craniata. (First Fascicle; Cyclostomes and Fishes) (Adam and Charles Black, 1909)." href="/articles/ncomms1355#ref-CR3" id="ref-link-section-d228159420e604">3</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Goodrich, E. S. Studies on the Structure and Development of Vertebrates (McMillan, 1930)." href="/articles/ncomms1355#ref-CR4" id="ref-link-section-d228159420e607">4</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Kent, G. C. & Carr, R. K. Comparative Anatomy of the Vertebrates (McGraw-Hill, 2001)." href="/articles/ncomms1355#ref-CR5" id="ref-link-section-d228159420e610">5</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Ayers, H. & Jackson, C. M. Morphology of the myxinoidei. I. Skeleton and musculature. J. Morphol. 17, 185–226 (1900)." href="/articles/ncomms1355#ref-CR18" id="ref-link-section-d228159420e613">18</a></sup>.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1" data-title="The putative vertebral elements of E. burgeri."><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 1: The putative vertebral elements of <i>E. burgeri</i>.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/ncomms1355/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fncomms1355/MediaObjects/41467_2011_Article_BFncomms1355_Fig1_HTML.jpg?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fncomms1355/MediaObjects/41467_2011_Article_BFncomms1355_Fig1_HTML.jpg" alt="figure 1" loading="lazy" width="685" height="684"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p>(<b>a</b>) Lateral views of whole-mount Alcian blue-stained adult hagfish. Anterior is to the left. (<b>b</b>) This high-magnification view of the caudal fin area shows small cartilaginous nodules (the putative vertebral elements) located on the ventral side of the notochord at the post-cloacal level (arrowheads). More posteriorly, dorsal and ventral fin rays are connected with median cartilaginous plates, previously called 'median dorsal and ventral bars'<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Ayers, H. & Jackson, C. M. Morphology of the myxinoidei. I. Skeleton and musculature. J. Morphol. 17, 185–226 (1900)." href="/articles/ncomms1355#ref-CR18" id="ref-link-section-d228159420e639">18</a></sup>. (<b>c</b>–<b>e</b>) Transverse views of paraffin sections of <i>E. burgeri</i> stained with haematoxylin and eosin and Alcian blue. (<b>c</b>) The putative vertebral elements (arrowheads) are located ventral to the notochord surrounding the dorsal aorta at the post-cloacal region. (<b>d</b>) Higher magnification of the box shown in <b>c</b>. (<b>e</b>) The median dorsal bar is attached to a pair of cartilaginous arches on both sides of the notochord at the caudalmost level (arrow). ao, dorsal aorta; cl, cloaca; fr, fin ray; mdb, median dorsal bar; mu, mucus gland; mvb, median ventral bar; n, notochord; nsh, notochordal sheath; nt, neural tube; ve, vein. Scale bars, 1 cm (<b>a</b>); 1 mm (<b>b</b>); 100 μm (<b>c</b>–<b>e</b>).</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/ncomms1355/figures/1" data-track-dest="link:Figure1 Full size image" aria-label="Full size image figure 1" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-2" data-title="Comparison of axial skeletal elements."><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 2: Comparison of axial skeletal elements.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/ncomms1355/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fncomms1355/MediaObjects/41467_2011_Article_BFncomms1355_Fig2_HTML.jpg?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fncomms1355/MediaObjects/41467_2011_Article_BFncomms1355_Fig2_HTML.jpg" alt="figure 2" loading="lazy" width="685" height="1155"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-2-desc"><p>(<b>a</b>–<b>f</b>) Transverse and horizontal sections of a whole-mount hagfish (<i>E. burgeri</i>), a lamprey (<i>Lethenteron japonicum</i>) and a catshark (<i>Galeus nipponesis</i>). (<b>a</b>) A transverse view of <i>E. burgeri</i>. (<b>b</b>) Ventral view of a horizontally sectioned <i>E. burgeri</i> specimen. (<b>c</b>) Transverse view of <i>L. japonicum</i>. (<b>d</b>) Ventral view of a horizontally sectioned <i>L. japonicum</i> specimen. (<b>e</b>) Transverse view of <i>G. nipponesis</i>. (<b>f</b>) Ventral view of a horizontally sectioned <i>G. nipponesis</i> specimen. The levels of the horizontal sections in each specimen are indicated by arrows in <b>a</b>, <b>c</b>, and <b>e</b>. The ventral view of the horizontally sectioned <i>E. burgeri</i> (<b>b</b>) shows an asymmetric and non-metameric distribution of cartilaginous nodules along the anterior–posterior axis. Myosepta are indicated by broken lines. The dorsal view of the sectioned lamprey (<b>d</b>) shows dorsal vertebral elements segmentally arranged in register with myomeres. The ventral view of the horizontal section of the shark (<b>f</b>) shows a clear metameric distribution of the hemal arches. These horizontal sections of the lamprey and the shark show that two cartilaginous nodules are located between two myosepta along the anterior–posterior axis (<b>d</b>, <b>f</b>). ao, dorsal aorta; ce, centrum; fr, fin ray; hem, hemal arch; n, notochord; nsh, notochordal sheath; nt, neural tube; ve, vein. Scale bars, 1 mm.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/ncomms1355/figures/2" data-track-dest="link:Figure2 Full size image" aria-label="Full size image figure 2" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><h3 class="c-article__sub-heading" id="Sec4">Somites and their derivatives</h3><p>To examine possible developmental similarities in putative vertebral elements between the hagfish and gnathostome vertebrae, we observed their embryonic development. Although we previously succeeded in collecting several early-stage hagfish embryos<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Ota, K. G., Kuraku, S. & Kuratani, S. Hagfish embryology with reference to the evolution of the neural crest. Nature 446, 672–675 (2007)." href="/articles/ncomms1355#ref-CR20" id="ref-link-section-d228159420e797">20</a></sup>, these were insufficient to trace the developmental processes of the somites and their derivatives. Hence, we conducted long-term incubation of fertilized hagfish eggs (Methods), and obtained 42 fertilized eggs at various developmental stages (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/ncomms1355#MOESM344">Supplementary Table S1</a>). We selected three different stages of hagfish embryo, designated the early-, middle-, and late-pharyngula stages, for analysis of somite development (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig3">Fig. 3</a>; <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/ncomms1355#MOESM344">Supplementary Table S1</a>). We used these three embryos to conduct detailed histological observations and used <i>in situ</i> hybridization to detect expression of <i>Twist</i> and <i>Pax1/9</i> homologues (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig3">Figs 3</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">4a–l</a>; <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/ncomms1355#MOESM344">Supplementary Figs S2</a> and <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/ncomms1355#MOESM344">S3</a>), known to be specifically expressed in the sclerotomes of some gnathostomes<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Christ, B., Huang, R. & Scaal, M. Formation and differentiation of the avian sclerotome. Anat. Embryol. 208, 333–350 (2004)." href="/articles/ncomms1355#ref-CR12" id="ref-link-section-d228159420e833">12</a></sup>.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3" data-title="Three stages of E. burgeri embryos."><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 3: Three stages of <i>E. burgeri</i> embryos.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/ncomms1355/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fncomms1355/MediaObjects/41467_2011_Article_BFncomms1355_Fig3_HTML.jpg?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fncomms1355/MediaObjects/41467_2011_Article_BFncomms1355_Fig3_HTML.jpg" alt="figure 3" loading="lazy" width="685" height="408"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-3-desc"><p>(<b>a</b>–<b>c</b>) Whole-mount cleared embryos of <i>E. burgeri</i>: (<b>a</b>) dorsal view of a 121 dpd embryo (early pharyngula); (<b>b</b>) dorsal view of a 145 dpd embryo (middle pharyngula); (<b>c</b>) lateral view of a 150 dpd embryo (late pharyngula) with tentacles and laterally flattened tail. (<b>d</b>–<b>f</b>) High-magnification view of the caudal regions: (<b>d</b>) early pharyngula embryo showing an epithelial somite; (<b>e</b>) middle pharyngula embryo; (<b>f</b>) late pharyngula embryo. Dotted lines indicate the levels of sections shown in <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig3">Figure 3a–j</a>. mu, mucus gland; nt, neural tube; som, somite; tent, tentacles. Scale bars, 1 mm (<b>a</b>–<b>c</b>); 100 μm (<b>d</b>–<b>f</b>).</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/ncomms1355/figures/3" data-track-dest="link:Figure3 Full size image" aria-label="Full size image figure 3" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-4" data-title="Somite derivatives of E. burgeri."><figure><figcaption><b id="Fig4" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 4: Somite derivatives of <i>E. burgeri</i>.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/ncomms1355/figures/4" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fncomms1355/MediaObjects/41467_2011_Article_BFncomms1355_Fig4_HTML.jpg?as=webp"><img aria-describedby="Fig4" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fncomms1355/MediaObjects/41467_2011_Article_BFncomms1355_Fig4_HTML.jpg" alt="figure 4" loading="lazy" width="685" height="1784"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-4-desc"><p>(<b>a</b>–<b>f</b>) Early pharyngula. (<b>a</b>) Epithelial somite in the caudalmost region of the trunk. (<b>b</b>) <i>Twist</i> is strongly expressed in the ventral somite. (<b>c</b>) <i>Pax1/9</i> is weakly expressed in the median ventral somite. (<b>d</b>) Sagittal section showing rostrocaudally migrating putative sclerotomal cells at the anterior level of the trunk. (<b>e</b>, <b>f</b>) Transverse sections at the anterior level of the trunk showing migrating putative sclerotomal cells expressing <i>Twist</i> (<b>e</b>) and <i>Pax1/9</i> (<b>f</b>) (arrowheads). (<b>g</b>–<b>j</b>) Middle pharyngula. (<b>g</b>) Mesenchymal cells located at the lateral side of the notochord. (<b>h</b>) <i>Pax1/9</i> expression by mesenchymal cells. (<b>i</b>) <i>Pax3/7</i> expression on the lateral side of a somite. (<b>j</b>) <i>MyoD</i> is strongly expressed at the medial side of a somite. (<b>k</b>, <b>l</b>) Late pharyngula. (<b>k</b>) Mesenchymal cells located at the dorsal aorta and the lateral side of the notochord. (<b>l</b>) Clear expression of <i>Pax1/9</i> is evident in the late pharyngula. (<b>m</b>, <b>n</b>) Schematic summary of the development of putative vertebral elements. (<b>m</b>) Medial ventral somites differentiate into mesenchymal cells (blue) in the early pharyngula. (<b>n</b>) The mesenchymal cells differentiate into the cartilaginous nodules in the adult. ao, dorsal aorta; mu, mucus gland; n, notochord; nt, neural tube; sc, sclerotome; som, somite. Arrows indicate the migrating sclerotomes. Scale bars, 100 μm.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/ncomms1355/figures/4" data-track-dest="link:Figure4 Full size image" aria-label="Full size image figure 4" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>The early pharyngula of the hagfish developed less than 80 somites, which showed several different phases that enabled us to investigate the somitic differentiation process along the anterior–posterior embryonic axis (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig3">Figs 3a,d</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">4a–f</a>). At the level of the 60th to 70th somites, the ventromedial region of the epithelial somite, located at the lateral aspect of the notochord, expressed <i>Twist</i> and <i>Pax1/9</i> genes (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4b,c</a>), and at the level of the 30th to 40th somites, mesenchymal cells expressed the same genes at the ventromedial side around the notochord (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4d–f</a>). We also observed that these mesenchymal cells (ventromedial cells) are subdivided into rostral and caudal populations, showing metameric patterning (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4d</a>), as in some gnathostome sclerotomes<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Goodrich, E. S. Studies on the Structure and Development of Vertebrates (McMillan, 1930)." href="/articles/ncomms1355#ref-CR4" id="ref-link-section-d228159420e1061">4</a></sup>. However, this segmental pattern did not appear to be maintained in the adult cartilaginous state, as noted above (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig2">Fig. 2a,b</a>).</p><p>Most of the trunk somites had formed by the middle pharyngula stage (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig3">Fig. 3b</a>). We thus observed caudal somite derivatives (80th somite level) in the prospective post-cloacal region wherein the putative vertebrae differentiate (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig3">Fig. 3e</a>). Histological observations at the caudal levels in this stage showed epithelial somites and mesenchymal cells at the lateral aspect of the neural tube and notochord (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4g</a>). Expression of <i>Pax1/9</i> and <i>Twist</i> were also observed in those cells at caudal levels in the middle pharyngula stage (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4h</a>). In particular, <i>Twist</i> expression was observed extensively in mesenchyme ventral to the notochord (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/ncomms1355#MOESM344">Supplementary Fig. S4</a>), whereas <i>Pax1/9</i> expression was restricted to the abovementioned ventromedial cells at the caudal level in this stage (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4h</a>). The dorsolateral epithelial portion of the somites consistently expressed <i>Pax3/7</i> and <i>MyoD</i>, which are expressed in the dermomyotome and myotome, respectively, in gnathostomes (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4i,j</a>; <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/ncomms1355#MOESM344">Supplementary Fig. S5</a>)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Goulding, M. D., Chalepakis, G., Deutsch, U., Erselius, J. R. & Gruss, P. Pax-3, a novel murine DNA binding protein expressed during early neurogenesis. EMBO. J. 10, 1135–1147 (1991)." href="/articles/ncomms1355#ref-CR21" id="ref-link-section-d228159420e1115">21</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Rudnicki, M. A. et al. MyoD or Myf-5 is required for the formation of skeletal muscle. Cell. 75, 1351–1359 (1993)." href="/articles/ncomms1355#ref-CR22" id="ref-link-section-d228159420e1118">22</a></sup>. These two genes showed mutually exclusive expression in these mesodermal cells. Similar to their gnathostome cognates<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Goulding, M. D., Chalepakis, G., Deutsch, U., Erselius, J. R. & Gruss, P. Pax-3, a novel murine DNA binding protein expressed during early neurogenesis. EMBO. J. 10, 1135–1147 (1991)." href="/articles/ncomms1355#ref-CR21" id="ref-link-section-d228159420e1122">21</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Rudnicki, M. A. et al. MyoD or Myf-5 is required for the formation of skeletal muscle. Cell. 75, 1351–1359 (1993)." href="/articles/ncomms1355#ref-CR22" id="ref-link-section-d228159420e1125">22</a></sup>, <i>Pax3/7</i> expression was detected in the lateral part of the somites, whereas <i>MyoD</i> expression was restricted to the medioventral region (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4i,j</a>). This shows that dermomyotome and myotomal primodia can be identified as derivatives of a hagfish somite, with corresponding gene expression patterns and in comparable mediolateral relative positions to those in gnathostomes (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4i,j</a>)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Goulding, M. D., Chalepakis, G., Deutsch, U., Erselius, J. R. & Gruss, P. Pax-3, a novel murine DNA binding protein expressed during early neurogenesis. EMBO. J. 10, 1135–1147 (1991)." href="/articles/ncomms1355#ref-CR21" id="ref-link-section-d228159420e1142">21</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Rudnicki, M. A. et al. MyoD or Myf-5 is required for the formation of skeletal muscle. Cell. 75, 1351–1359 (1993)." href="/articles/ncomms1355#ref-CR22" id="ref-link-section-d228159420e1145">22</a></sup>. Furthermore, these are found at the same axial level as that from which the putative vertebral elements are formed (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig1">Fig. 1b</a>). This strongly suggests that the <i>Pax1/9</i>-positive mesenchymal cells at the ventromedial aspect of the somite epithelia were developmentally equivalent to the sclerotome in gnathostomes (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4h</a>)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Christ, B., Huang, R. & Scaal, M. Formation and differentiation of the avian sclerotome. Anat. Embryol. 208, 333–350 (2004)." href="/articles/ncomms1355#ref-CR12" id="ref-link-section-d228159420e1159">12</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Goulding, M. D., Chalepakis, G., Deutsch, U., Erselius, J. R. & Gruss, P. Pax-3, a novel murine DNA binding protein expressed during early neurogenesis. EMBO. J. 10, 1135–1147 (1991)." href="/articles/ncomms1355#ref-CR21" id="ref-link-section-d228159420e1162">21</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Rudnicki, M. A. et al. MyoD or Myf-5 is required for the formation of skeletal muscle. Cell. 75, 1351–1359 (1993)." href="/articles/ncomms1355#ref-CR22" id="ref-link-section-d228159420e1165">22</a></sup>.</p><p>At the 90th somite level in the late pharyngula (the level of the vertebra-like elements; see <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig3">Fig. 3c,f</a>), <i>Pax1/9</i>-positive cells were distributed in more extensive domains than those in the previous embryo, with clusters detectable at the ventrolateral aspect of the notochord (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig3">Fig. 3k,l</a>). This led us to infer that these <i>Pax1/9</i>-positive cells may migrate further ventrally, surrounding the dorsal aorta, to differentiate into cartilaginous tissues on the ventral aspect of the notochord in later embryos (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4m,n</a>). Given the metameric distribution patterns of the mesenchymal cells at the early pharyngula stage (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4d</a>), the segmentally arranged sclerotomes, which originate from the ventromedial part of the somite (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4a–c,e,f</a>), are likely to form the putative vertebral elements found in the adult (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig1">Fig. 1</a>) via molecular mechanisms common to those in gnathostomes (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4m,n</a>)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Christ, B., Huang, R. & Scaal, M. Formation and differentiation of the avian sclerotome. Anat. Embryol. 208, 333–350 (2004)." href="/articles/ncomms1355#ref-CR12" id="ref-link-section-d228159420e1200">12</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Goulding, M. D., Chalepakis, G., Deutsch, U., Erselius, J. R. & Gruss, P. Pax-3, a novel murine DNA binding protein expressed during early neurogenesis. EMBO. J. 10, 1135–1147 (1991)." href="/articles/ncomms1355#ref-CR21" id="ref-link-section-d228159420e1203">21</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Rudnicki, M. A. et al. MyoD or Myf-5 is required for the formation of skeletal muscle. Cell. 75, 1351–1359 (1993)." href="/articles/ncomms1355#ref-CR22" id="ref-link-section-d228159420e1206">22</a></sup>. These results suggest that despite the minute size and disrupted segmental pattern of the putative vertebral elements in hagfish (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig1">Fig. 1b–e</a>), they can be homologous to vertebrae.</p></div></div></section><section data-title="Discussion"><div class="c-article-section" id="Sec5-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec5">Discussion</h2><div class="c-article-section__content" id="Sec5-content"><p>From the above observations, it seems plausible to assume that all the hagfish somites form sclerotomes and dermomyotomes at all axial levels in positions corresponding to those in gnathostomes, and that these somatic components arise via molecular developmental mechanisms similar to those in gnathostome embryos (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig4">Fig. 4</a>). At the post-cloacal level, the sclerotome-derived cells are distributed in regions prospectively occupied by the vestigial cartilaginous nodules in adults. Thus, in the hagfish, the somite appears to respond to signals derived from the notochord to specify cells destined towards skeletal differentiation. In this connection, the potential skeletogenic property of hagfish paraxial mesoderm is suggested in the chordal cranium (the caudal portion of the neurocranium known as the parachordals; <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/ncomms1355#MOESM344">Supplementary Fig. S6</a>)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Couly, G. F., Coltey, P. M. & Le Douarin, N. M. The triple origin of skull in higher vertebrates: a study in quail-chick chimeras. Development 117, 409–429 (1993)." href="/articles/ncomms1355#ref-CR23" id="ref-link-section-d228159420e1228">23</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Kuratani, S. & Ota, K. G. Primitive versus derived traits in the developmental program of the vertebrate head: views from cyclostome developmental studies. J. Exp. Zool. B Mol. Dev. Evol. 310B, 294–314 (2008)." href="/articles/ncomms1355#ref-CR24" id="ref-link-section-d228159420e1231">24</a></sup>. Therefore, it seems likely that the notochordally derived signal is primarily capable of inducing chondrification in the paraxial mesoderm of the hagfish, and that this mechanism is lost secondarily from the pre-cloacal part of the hagfish trunk.</p><p>Our observations are consistent at the anatomical and developmental level with the presence of axial cartilage in hagfish that is homologous to gnathostome vertebrae. This indicates that the presence of cartilaginous axial skeletal elements can be considered as a characteristic common to gnathostomes, lampreys and hagfishes. Hence, we can no longer exclude the hagfish from the Vertebrata simply due to the absence of a cartilaginous axial skeleton, which has now been disproved (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig5">Fig. 5</a>).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-5" data-title="Hypothetical scenario of vertebral evolution."><figure><figcaption><b id="Fig5" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 5: Hypothetical scenario of vertebral evolution.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/ncomms1355/figures/5" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fncomms1355/MediaObjects/41467_2011_Article_BFncomms1355_Fig5_HTML.jpg?as=webp"><img aria-describedby="Fig5" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fncomms1355/MediaObjects/41467_2011_Article_BFncomms1355_Fig5_HTML.jpg" alt="figure 5" loading="lazy" width="685" height="531"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-5-desc"><p>This phylogenetic tree is based mainly on molecular data and hagfishes are clustered with lampreys as members of monophyletic cyclostomes<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Mallatt, J. & Sullivan, J. 28S and 18S rDNA sequences support the monophyly of lampreys and hagfishes. Mol. Biol. Evol. 15, 1706–1718 (1998)." href="/articles/ncomms1355#ref-CR25" id="ref-link-section-d228159420e1253">25</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Kuraku, S., Hoshiyama, D., Katoh, K., Suga, H. & Miyata, T. Monophyly of lampreys and hagfishes supported by nuclear DNA-coded genes. J. Mol. Evol. 49, 729–735 (1999)." href="/articles/ncomms1355#ref-CR26" id="ref-link-section-d228159420e1256">26</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Takezaki, N., Figueroa, F., Zaleska-Rutczynska, Z. & Klein, J. Molecular phylogeny of early vertebrates: monophyly of the agnathans as revealed by sequences of 35 genes. Mol. Biol. Evol. 20, 287–292 (2003)." href="/articles/ncomms1355#ref-CR27" id="ref-link-section-d228159420e1259">27</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Heimberg, A. M., Cowper-Sal-lari, R., Sémon, M., Donoghue, P. C. J. & Peterson, K. J. microRNAs reveal the interrelationships of hagfish, lampreys, and gnathostomes and the nature of the ancestral vertebrate. Proc. Natl Acad. Sci. USA 107, 19379–19383 (2010)." href="/articles/ncomms1355#ref-CR28" id="ref-link-section-d228159420e1262">28</a></sup>. The origins of the cartilaginous vertebrae, consisting of dorsal and ventral elements, as well as associated developmental mechanisms are assumed to have been obtained before the divergence of gnathostomes, lampreys, and hagfish. The vertebral elements of the extant vertebrates are coloured blue, and those of the common ancestor of entire extant vertebrates are indicated by dotted lines. bd, basi-dorsal; bv, basi-ventral; id, inter-dorsal; iv, inter-dorsal; n, notochord; nt, neural tube.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/ncomms1355/figures/5" data-track-dest="link:Figure5 Full size image" aria-label="Full size image figure 5" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Although our developmental study suggested a sclerotomal origin for the ventral elements, the origin of the dorsal element, reminiscent of the neural arches and spine of gnathostomes, remains unclear (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig1">Fig. 1b</a>). Nevertheless, given the anatomical similarity of this element to the gnathostome counterpart (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig1">Figs 1e</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig2">2e,f</a>), it is highly possible that they share the same developmental patterns, suggesting that the paraxial mesoderm of the entire common ancestor of gnathostomes, lampreys and hagfishes could form cartilaginous elements on both the dorsal and ventral sides of the notochord. Taking into account the recently reconstructed phylogenetic trees based on molecular data, which support a monophyly of hagfishes and lampreys<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Mallatt, J. & Sullivan, J. 28S and 18S rDNA sequences support the monophyly of lampreys and hagfishes. Mol. Biol. Evol. 15, 1706–1718 (1998)." href="/articles/ncomms1355#ref-CR25" id="ref-link-section-d228159420e1286">25</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Kuraku, S., Hoshiyama, D., Katoh, K., Suga, H. & Miyata, T. Monophyly of lampreys and hagfishes supported by nuclear DNA-coded genes. J. Mol. Evol. 49, 729–735 (1999)." href="/articles/ncomms1355#ref-CR26" id="ref-link-section-d228159420e1289">26</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Takezaki, N., Figueroa, F., Zaleska-Rutczynska, Z. & Klein, J. Molecular phylogeny of early vertebrates: monophyly of the agnathans as revealed by sequences of 35 genes. Mol. Biol. Evol. 20, 287–292 (2003)." href="/articles/ncomms1355#ref-CR27" id="ref-link-section-d228159420e1292">27</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Heimberg, A. M., Cowper-Sal-lari, R., Sémon, M., Donoghue, P. C. J. & Peterson, K. J. microRNAs reveal the interrelationships of hagfish, lampreys, and gnathostomes and the nature of the ancestral vertebrate. Proc. Natl Acad. Sci. USA 107, 19379–19383 (2010)." href="/articles/ncomms1355#ref-CR28" id="ref-link-section-d228159420e1295">28</a></sup>, it seems reasonable to hypothesize that the dorsal and ventral vertebral elements were obtained from a common ancestor of the entire vertebrates, and that subsequent secondary losses would have led to loss of the dorsal vertebral elements in the hagfishes on one hand, and to a ventral vertebral element in the lamprey on the other (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig5">Fig. 5</a>). To test this hypothesis, further comparative developmental studies will be required to exclude the possibility of independent evolutionary occurrence of vertebral elements in the extant agnathan lineages, because it is still unclear whether the entire part of the vertebral elements of extant agnathans is derived from sclerotomal cells, as occurs in gnathostomes<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Christ, B., Huang, R. & Scaal, M. Formation and differentiation of the avian sclerotome. Anat. Embryol. 208, 333–350 (2004)." href="/articles/ncomms1355#ref-CR12" id="ref-link-section-d228159420e1303">12</a></sup>. We still cannot rule out completely the possibility that some parts of the vertebral elements of lamprey and hagfish are derived from non-sclerotomal cells (for example, neural crest cells).</p><p>Finally, it remains to be determined whether the morphological pattern of hagfish axial skeletal elements represents a secondary loss of segmentation or an ancestral state before acquisition of the segmental pattern. However, the former scenario is more plausible under the assumption of the monophyly of the extant agnathans (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig5">Fig. 5</a>). This scenario implies that the common ancestor of the extant gnathostomes and agnathans had the developmental mechanism to form a segmental axial skeleton consisting of two topographically different cartilaginous nodules, one located at the level of the myoseptum and the other at the intermediate level between the two myosepta, along the anterior–posterior axis, as seen in the vertebral elements of lampreys and gnathostomes (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig2">Figs 2</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig5">5</a>). The origin of this developmental mechanism could date back to around 500 million years ago based on the divergence time between agnathans and gnathostomes<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Kuraku, S., Hoshiyama, D., Katoh, K., Suga, H. & Miyata, T. Monophyly of lampreys and hagfishes supported by nuclear DNA-coded genes. J. Mol. Evol. 49, 729–735 (1999)." href="/articles/ncomms1355#ref-CR26" id="ref-link-section-d228159420e1319">26</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Takezaki, N., Figueroa, F., Zaleska-Rutczynska, Z. & Klein, J. Molecular phylogeny of early vertebrates: monophyly of the agnathans as revealed by sequences of 35 genes. Mol. Biol. Evol. 20, 287–292 (2003)." href="/articles/ncomms1355#ref-CR27" id="ref-link-section-d228159420e1322">27</a></sup>. Also problematic is the absence of cartilaginous tissue from the pre-cloacal trunk, as well as the absence of dorsal skeletal elements in most of the post-cloacal region (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/ncomms1355#Fig1">Fig. 1</a>). Further study is required to elucidate whether such a loss can be simply explained by adaptation to a hagfish lifestyle or by the long evolutionary period<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Kardong, K. V. Vertebrates Comparative Anatomy, Function, Evolution (McGraw-Hill Higher Education, 2008)." href="/articles/ncomms1355#ref-CR2" id="ref-link-section-d228159420e1330">2</a></sup>. The origin of the axial skeleton remains an issue in evolutionary developmental biology, and will require consideration of paleontological, embryological and molecular data<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Christ, B., Huang, R. & Scaal, M. Formation and differentiation of the avian sclerotome. Anat. Embryol. 208, 333–350 (2004)." href="/articles/ncomms1355#ref-CR12" id="ref-link-section-d228159420e1334">12</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Zhang, G., Miyamoto, M. M. & Cohn, M. J. Lamprey type II collagen and Sox9 reveal an ancient origin of the vertebrate collagenous skeleton. Proc. Natl Acad. Sci. USA 103, 3180–3185 (2006)." href="/articles/ncomms1355#ref-CR13" id="ref-link-section-d228159420e1337">13</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Mallatt, J. & Sullivan, J. 28S and 18S rDNA sequences support the monophyly of lampreys and hagfishes. Mol. Biol. Evol. 15, 1706–1718 (1998)." href="/articles/ncomms1355#ref-CR25" id="ref-link-section-d228159420e1340">25</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Kuraku, S., Hoshiyama, D., Katoh, K., Suga, H. & Miyata, T. Monophyly of lampreys and hagfishes supported by nuclear DNA-coded genes. J. Mol. Evol. 49, 729–735 (1999)." href="/articles/ncomms1355#ref-CR26" id="ref-link-section-d228159420e1343">26</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Takezaki, N., Figueroa, F., Zaleska-Rutczynska, Z. & Klein, J. Molecular phylogeny of early vertebrates: monophyly of the agnathans as revealed by sequences of 35 genes. Mol. Biol. Evol. 20, 287–292 (2003)." href="/articles/ncomms1355#ref-CR27" id="ref-link-section-d228159420e1346">27</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Heimberg, A. M., Cowper-Sal-lari, R., Sémon, M., Donoghue, P. C. J. & Peterson, K. J. microRNAs reveal the interrelationships of hagfish, lampreys, and gnathostomes and the nature of the ancestral vertebrate. Proc. Natl Acad. Sci. USA 107, 19379–19383 (2010)." href="/articles/ncomms1355#ref-CR28" id="ref-link-section-d228159420e1349">28</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Janvier, P. & Arsenault, M. Palaeobiology: calcification of early vertebrate cartilage. Nature 417, 609 (2002)." href="/articles/ncomms1355#ref-CR29" id="ref-link-section-d228159420e1353">29</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Shu, D. et al. Head and backbone of the Early Cambrian vertebrate Haikouichthys. Nature 421, 526–529 (2003)." href="/articles/ncomms1355#ref-CR30" id="ref-link-section-d228159420e1356">30</a></sup>. We are hopeful that further advances in hagfish embryology will provide more insights into the evolution of the axial skeletal element in the early vertebrates, especially into the origin of its segmental pattern.</p></div></div></section><section data-title="Methods"><div class="c-article-section" id="Sec6-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec6">Methods</h2><div class="c-article-section__content" id="Sec6-content"><h3 class="c-article__sub-heading" id="Sec7">Sample collection and aquarium maintenance</h3><p>Adult males and females of <i>E. burgeri</i> were collected using eel traps from a depth of 25–100 m in the Japan Sea off the Shimane and Yamaguchi prefectures during September and October. After the hagfish were transferred to a laboratory aquarium (at 16 °C) and sexed by manipulation, about 100 adult specimens were maintained in an aquarium tank lined with potentially favourable substrates, including fine-grain sand and oyster shells (1,000 l, 16–17 °C) (refs <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Ota, K. G. & Kuratani, S. The history of scientific endeavors towards understanding hagfish embryology. Zoolog. Sci. 23, 403–418 (2006)." href="/articles/ncomms1355#ref-CR31" id="ref-link-section-d228159420e1374">31</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Ota, K. G. & Kuratani, S. Developmental biology of hagfishes, with a report on newly obtained embryos of the Japanese inshore hagfish, Eptatretus burgeri. Zoolog. Sci. 25, 999–1011 (2008)." href="/articles/ncomms1355#ref-CR32" id="ref-link-section-d228159420e1377">32</a>). The deposited eggs were individually incubated in a plastic container (4 cm×4 cm×5 cm) in the same aquarium tank<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Ota, K. G. & Kuratani, S. Developmental biology of hagfishes, with a report on newly obtained embryos of the Japanese inshore hagfish, Eptatretus burgeri. Zoolog. Sci. 25, 999–1011 (2008)." href="/articles/ncomms1355#ref-CR32" id="ref-link-section-d228159420e1381">32</a></sup>. Fertilized eggs were identified by visual inspection and were prepared for further analysis. All of the embryos are listed in <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/ncomms1355#MOESM344">Supplementary Table S1</a>.</p><h3 class="c-article__sub-heading" id="Sec8">Molecular cloning</h3><p>Total RNA was extracted from embryos using TRIZOL reagent (Invitrogen). Degenerated RT–PCR was performed to amplify fragments of <i>Twist</i>, <i>Pax1/9</i>, and <i>MyoD</i> messenger RNA using the primer sets listed in <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/ncomms1355#MOESM344">Supplementary Table S2</a>. These fragments were isolated using the TOPO TA Cloning Kit Dual Promoter (Invitrogen) and sequenced using an ABI 3130XL automated sequencer (Applied Biosystems). The sequence data were submitted to the DDBJ database (AB594746, AB594747, AB594748). To identify the orthologous genes of the isolated fragments, comparable sequence data were surveyed using the NCBI protein database and a BLAST search, and multiple sequence alignments were generated using the CLUSTALW multiple alignment program<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Thompson, J. D., Higgins, D. G. & Gibson, T. J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22, 4673–4680 (1994)." href="/articles/ncomms1355#ref-CR33" id="ref-link-section-d228159420e1408">33</a></sup>. Multiple sequence alignments were corrected by visual inspection. Based on these alignments, gene-specific residues and motifs were identified (<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/ncomms1355#MOESM344">Supplementary Figs S3</a>, <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/ncomms1355#MOESM344">S4</a>, <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/ncomms1355#MOESM344">S6</a>).</p><h3 class="c-article__sub-heading" id="Sec9">Histology and <i>in situ</i> hybridization</h3><p>Hagfish specimens were fixed in Serra's fixatives for 24–48 h, dehydrated using an ethanol series, placed in xylene, embedded in paraffin, and sliced at a thickness of 8 μm. The sliced sections were deparaffinized and stained with haematoxylin, eosin and Alcian blue<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Ota, K. G. & Kuratani, S. Expression pattern of two collagen type 2 α1 genes in the Japanese inshore hagfish (Eptatretus burgeri) with special reference to the evolution of cartilaginous tissue. J. Exp. Zool. B Mol. Dev. Evol. 314B, 157–165 (2010)." href="/articles/ncomms1355#ref-CR34" id="ref-link-section-d228159420e1434">34</a></sup>. <i>In situ</i> hybridization was carried out using a Ventana automated machine (Ventana Medical Systems). Detection of signals and counterstaining were performed using the BlueMap NBT/BCIP substrate kit and the nuclear fast red equivalent reagent, ISH RED (Ventana).</p></div></div></section><section data-title="Additional information"><div class="c-article-section" id="Sec10-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec10">Additional information</h2><div class="c-article-section__content" id="Sec10-content"><p><b>Accession codes:</b> The sequence data have been deposited to the DDBJ database under accession codes <a href="http://getentry.ddbj.nig.ac.jp/getentry?database=ddbj&accession_number=AB594746">AB594746</a>, <a href="http://getentry.ddbj.nig.ac.jp/getentry?database=ddbj&accession_number=AB594747">AB594747</a> and <a href="http://getentry.ddbj.nig.ac.jp/getentry?database=ddbj&accession_number=AB594748">AB594748</a>.</p><p><b>How to cite this article:</b> Ota, K. G. <i>et al</i>. Identification of vertebra-like elements and their possible differentiation from sclerotomes in the hagfish. <i>Nat. Commun.</i> 2:373 doi: 10.1038/ncomms1355 (2011).</p></div></div></section> </div> <div> <section data-title="Accession codes"><div class="c-article-section" id="accession-codes-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="accession-codes">Accession codes</h2><div class="c-article-section__content" id="accession-codes-content"> <h3 class="c-article__sub-heading">Accessions</h3> <h4 class="c-article__sub-heading c-article__sub-heading--small">DDBJ/GenBank/EMBL</h4><ul class="c-article-data-availability-list u-list-reset"> <li class="c-article-data-availability-list__item"> <p> <a href="http://getentry.ddbj.nig.ac.jp/getentry?database=ddbj&accession_number=AB594746">AB594746</a> </p> </li> <li class="c-article-data-availability-list__item"> <p> <a href="http://getentry.ddbj.nig.ac.jp/getentry?database=ddbj&accession_number=AB594747">AB594747</a> </p> </li> <li class="c-article-data-availability-list__item"> <p> <a href="http://getentry.ddbj.nig.ac.jp/getentry?database=ddbj&accession_number=AB594748">AB594748</a> </p> </li> </ul> </div></div></section><div id="MagazineFulltextArticleBodySuffix"><section aria-labelledby="Bib1" data-title="References"><div class="c-article-section" id="Bib1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Bib1">References</h2><div class="c-article-section__content" id="Bib1-content"><div data-container-section="references"><ol class="c-article-references" data-track-component="outbound reference" data-track-context="references section"><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="1"><p class="c-article-references__text" id="ref-CR1">Janvier, P. <i>Early Vertebrates</i> (Oxford University Press, 1996).</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="2"><p class="c-article-references__text" id="ref-CR2">Kardong, K. 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Kakitani of Shimane fisheries cooperative, K. Yamada of Kotoku Inc., and K. Kayano of Sekikatu Inc. for sample collection, S. Aota, F. Sugahara, H. Nagashima, S. Kuraku, N. Adachi, and H. Higashiyama for their valuable advice, and R. Ladher and D. Sipp for critical reading of this manuscript. This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Laboratory for Evolutionary Morphology, RIKEN Center for Developmental Biology, Kobe, 650-0047, Japan</p><p class="c-article-author-affiliation__authors-list">Kinya G. Ota, Satoko Fujimoto, Yasuhiro Oisi & Shigeru Kuratani</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Marine Research Station, Institute of Cellular and Organismic Biology, Academia Sinica, Yilan, 26242, Taiwan</p><p class="c-article-author-affiliation__authors-list">Kinya G. Ota</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Kinya_G_-Ota-Aff1-Aff2"><span class="c-article-authors-search__title u-h3 js-search-name">Kinya G. 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S.F. was involved in the molecular cloning of the <i>Pax1/9</i>, <i>MyoD</i>, and <i>Twist</i> genes and in the <i>in situ</i> hybridization. K.G.O. performed the molecular evolutionary analysis. K.G.O. and S.K. wrote the manuscript. All authors discussed the results and commented on the manuscript.</p><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding author</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:otakinya@gate.sinica.edu.tw">Kinya G. 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Identification of vertebra-like elements and their possible differentiation from sclerotomes in the hagfish | Nature Communications