MorphologyMorphologyМорфология1026-35432949-2556Eco-Vector69823310.17816/morph.698233GUJEAOReviewsНаучные обзорыReview ArticleNotochord: morphogenesis, structure, and functional significanceХорда (нотохорд): морфогенез, структура и функциональное значение脊索：形态发生、结构与功能意义https://orcid.org/0000-0002-6909-89374072-3845SorochanuIrinaСорочануИринаSorochanuIrina
Russian Federation
ipsorochanu@gmail.comhttps://orcid.org/0000-0001-8389-38412957-1687DeevRoman V.ДеевРоман Вадимович
Russian Federation

MD, Cand. Sci. (Medicine), Assistant Professor

канд. мед. наук, доцент

MD, Cand. Sci. (Medicine), Assistant Professor

romdey@gmail.comPetrovsky National Research Centre of SurgeryРоссийский научный центр хирургии им. акад. Б.В. ПетровскогоPetrovsky National Research Centre of Surgery220120262303202616421291460912202530122025Copyright ©; 2026, Eco-VectorCopyright ©; 2026, Эко-ВекторCopyright ©; 2026,2026Eco-VectorЭко-Векторhttps://creativecommons.org/licenses/by-nc-nd/4.0/https://j-morphology.com/1026-3543/article/view/698233

The notochord represents a defining synapomorphy of the phylum Chordata, serving as the primary axial skeleton and a crucial embryonic organizer. This review systematizes current concepts regarding the evolutionary origin, molecular mechanisms of morphogenesis, and structural–functional organization of the notochord. Major evolutionary hypotheses — dorsoventral inversion and aboral dorsalization — are examined and compared in the context of vertebrate body plan formation.

The hierarchical gene regulatory network underlying notochord development is described in detail, with emphasis on the central role of the transcription factor TBXT (Brachyury) and the Wnt/PCP, Hedgehog, and Notch signaling pathways. Molecular and cellular mechanisms of convergent extension, formation of the perinotochordal sheath, and cellular vacuolization — processes that generate turgor pressure and mechanical stiffness — are analyzed. Particular attention is given to notochord formation in humans, from the stage of the notochordal plate to its postnatal transformation into the nucleus pulposus of the intervertebral discs.

The clinical relevance of residual progenitor cell populations within the nucleus pulposus expressing the markers Tie2 and GD2 is discussed. Their role in maintaining homeostasis within the avascular intervertebral disc, the association between depletion of this cell pool and the development of degenerative spinal disorders, and their potential applications in regenerative medicine are considered. The review also addresses issues related to the molecular diagnosis of chordoma as a tumor of notochordal origin.

Хорда (нотохорд) является определяющей синапоморфией типа Chordata, выполняющей роль первичного осевого скелета и важнейшего эмбрионального организатора. В данном обзоре систематизированы современные представления об эволюционном происхождении, молекулярных механизмах морфогенеза и структурно-функциональной организации хорды. Рассмотрены и сопоставлены основные эволюционные гипотезы — дорсовентральной инверсии и аборальной дорсализации, объясняющие формирование плана строения тела позвоночных.

Подробно описана иерархия генно-регуляторной сети, в которой ключевую роль играет транскрипционный фактор TBXT (Brachyury), а также сигнальные пути Wnt/PCP, Hedgehog и Notch. Проанализированы молекулярные и клеточные механизмы конвергентного растяжения, образования перихордальной оболочки и вакуолизации клеток, обеспечивающих тургорное давление и механическую жёсткость органа. Особое внимание уделено описанию формирования хорды у человека: от стадии хордальной пластинки до её постнатальной трансформации в студенистое (пульпозное) ядро межпозвонковых дисков.

В работе обсуждается клиническое значение резистентных популяций стволовых клеток-предшественников тканевых элементов пульпозного ядра, экспрессирующих маркеры Tie2 и GD2. Кроме того, рассмотрена роль этих клеток в поддержании гомеостаза в лишённом кровеносных сосудов межпозвонковом диске, связь между истощением их пула и развитием дегенеративных заболеваний позвоночника, а также перспективы их использования в регенеративной медицине. Также затронуты вопросы молекулярной диагностики хордомы как опухоли нотохордального происхождения.

脊索是脊索动物门的主要共有衍征，它作为主要的轴骨骼和最重要的胚胎组织者。本文系统阐述了关于脊索的进化起源、形态发生的分子机制以及结构和功能组织的现代概念。本文探讨并比较了解释脊椎动物体型形成的主要进化假说 — — 背腹反转和反口背化。

本文详细描述了基因调控网络的层级结构，其中转录因子TBXT（Brachyury）发挥着关键作用，并阐述了Wnt/PCP、Hedgehog和Notch信号通路。文章分析了趋同拉伸、脊索膜形成和细胞空泡化的分子和细胞机制，这些机制为器官提供膨压和机械刚度。文章重点描述了人类脊索的形成过程：从脊索板阶段到出生后转化为椎间盘胶状核（髓核）。

文章还探讨了表达Tie2和GD2标记的、作为髓核组织成分前体的抗性干细胞群的临床意义。此外，本文还探讨了这些细胞在维持无血管椎间盘稳态中的作用、其数量减少与脊柱退行性疾病发展之间的关系，以及它们在再生医学中的应用前景。文章还涉及脊索瘤（一种起源于脊索的肿瘤）的分子诊断问题。

chordamesodermnotochordphylogenyontogenynucleus pulposusTBXTBrachyurymorphogenesisintervertebral discchordomaхорданотохордфилогенезонтогенезстуденистое ядроTBXTBrachyuryморфогенезмежпозвонковый дискхордома脊索系统发育个体发育胶状核（髓核）TBXTBrachyury形态发生椎间盘脊索瘤Kardong KV. Vertebrates: comparative anatomy, function, evolution. 6th ed. New York: McGraw-Hill; 2012. ISBN: 978-0-07-352423-8Dzerzhinskii FYa, Vasilev BD, Malakhov VV. Vertebrate Zoology: a textbook for students of higher professional education institutions. Moscow: Izdatel’skii tsentr «Akademiia»; 2013. (In Russ.) ISBN: 978-5-7965-7971-4Annona G, Holland ND, D’Aniello S. Evolution of the notochord. Evodevo. 2015;6:30. doi: 10.1186/s13227-015-0025-3 EDN: TCBSLBStemple DL. Structure and function of the notochord: an essential organ for chordate development. Development. 2005;132(11):2503–2512. doi: 10.1242/dev.01812Corallo D, Trapani V, Bonaldo P. The notochord: structure and functions. Cell Mol Life Sci. 2015;72(16):2989–3008. doi: 10.1007/s00018-015-1897-z EDN: NEWUZORamesh T, Nagula SV, Tardieu GG, et al. Update on the notochord including its embryology, molecular development, and pathology: a primer for the clinician. Cureus. 2017;9(4):e1137. doi: 10.7759/cureus.1137Teillet MA, Lapointe F, Le Douarin NM. The relationships between notochord and floor plate in vertebrate development revisited. Proc Natl Acad Sci U S A. 1998;95(20):11733–11738. doi: 10.1073/pnas.95.20.11733Grotmol S, Kryvi H, Keynes R, et al. Stepwise enforcement of the notochord and its intersection with the myoseptum: an evolutionary path leading to development of the vertebra? J Anat. 2006;209(3):339–357. doi: 10.1111/j.1469-7580.2006.00618.xUrban JPG, Roberts S, Ralphs JR. The Nucleus of the Intervertebral Disc from Development to Degeneration. American Zoologist. 2000;40(1):53–061. doi: 10.1093/icb/40.1.53 EDN: IPNYUTDanos MC, Yost HJ. Role of notochord in specification of cardiac left-right orientation in zebrafish and Xenopus. Dev Biol. 1996;177(1):96–103. doi: 10.1006/dbio.1996.0148 EDN: BCPICLLohr JL, Danos MC, Yost HJ. Left-right asymmetry of a nodal-related gene is regulated by dorsoanterior midline structures during Xenopus development. Development. 1997;124(8):1465–1472. doi: 10.1242/dev.124.8.1465Grimes DT, Burdine RD. Left-right patterning: breaking symmetry to asymmetric morphogenesis. Trends Genet. 2017;33(9):616–628. doi: 10.1016/j.tig.2017.06.004Hadorn E, Vener R. General zoology. Moscow: Mir; 1989. (In Russ.)Satoh N, Rokhsar D, Nishikawa T. Chordate evolution and the three-phylum system. Proc Biol Sci. 2014;281(1794):20141729. doi: 10.1098/rspb.2014.1729Trapani V, Bonaldo P, Corallo D. Role of the ECM in notochord formation, function and disease. J Cell Sci. 2017;130(19):3203–3211. doi: 10.1242/jcs.175950Zavaleeva SM, Sizova EA, Chirkova EN. Evolutionary and functional morphology of animals. Orenburg: GOU OGU; 2007. (In Russ.)DeSai C, Jozsa F, Agarwal A. Neuroanatomy, spine. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [cited 2026 Jan 19]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK526133/Lauri A, Brunet T, Handberg-Thorsager M, et al. Development of the annelid axochord: insights into notochord evolution. Science. 2014;345(6202):1365–1368. doi: 10.1126/science.1253396 EDN: USKPVPBrunet T, Lauri A, Arendt D. Did the notochord evolve from an ancient axial muscle? The axochord hypothesis. Bioessays. 2015;37(8):836–850. doi: 10.1002/bies.201500027 EDN: UOOJKHMedeiros DM. Ancient origin for the axochord: a putative notochord homolog. Bioessays. 2015;37(8):834. doi: 10.1002/bies.201500075Lowe CJ, Terasaki M, Wu M, et al. Dorsoventral patterning in hemichordates: insights into early chordate evolution. PLoS Biol. 2006;4(9):e291. doi: 10.1371/journal.pbio.0040291Miyamoto N, Wada H. Hemichordate neurulation and the origin of the neural tube. Nat Commun. 2013;4:2713. doi: 10.1038/ncomms3713Ruppert EE. Key characters uniting hemichordates and chordates: homologies or homoplasies? Canadian Journal of Zoology. 2005;83(1):8–23. doi: 10.1139/z04-158 EDN: XRTRIGSatoh N, Tagawa K, Lowe CJ, et al. On a possible evolutionary link of the stomochord of hemichordates to pharyngeal organs of chordates. Genesis. 2014;52(12):925–934. doi: 10.1002/dvg.22831Nübler-Jung K, Arendt D. Enteropneusts and chordate evolution. Curr Biol. 1996;6(4):352–353. doi: 10.1016/s0960-9822(02)00491-8Lowe CJ, Wu M, Salic A, et al. Anteroposterior patterning in hemichordates and the origins of the chordate nervous system. Cell. 2003;113(7):853–865. doi: 10.1016/s0092-8674(03)00469-0 EDN: LXVELTLowe CJ. Molecular genetic insights into deuterostome evolution from the direct-developing hemichordate Saccoglossus kowalevskii. Philos Trans R Soc Lond B Biol Sci. 2008;363(1496):1569–1578. doi: 10.1098/rstb.2007.2247Lowe CJ, Clarke DN, Medeiros DM, et al. The deuterostome context of chordate origins. Nature. 2015;520(7548):456–465. doi: 10.1038/nature14434Satoh N. An aboral-dorsalization hypothesis for chordate origin. Genesis. 2008;46(11):614–622. doi: 10.1002/dvg.20416Satoh N, Tagawa K, Takahashi H. How was the notochord born? Evol Dev. 2012;14(1):56–75. doi: 10.1111/j.1525-142X.2011.00522.xde Bakker BS, de Jong KH, Hagoort J, et al. An interactive three-dimensional digital atlas and quantitative database of human development. Science. 2016;354(6315):aag0053. doi: 10.1126/science.aag0053 EDN: JBXVEBde Bakker BS. 3D atlas of human embryology: New insights in human development. Amsterdam: University of Amsterdam; 2018 [cited 2026 Jan 19]. Available from: https://pure.uva.nl/ws/files/20042022/0._Front_matter.pdfde Bree K, de Bakker BS, Oostra RJ. The development of the human notochord. PLoS One. 2018;13(10):e0205752. doi: 10.1371/journal.pone.0205752O’Rahilly R, Müller F. Developmental stages in human embryos: revised and new measurements. Cells Tissues Organs. 2010;192(2):73–84. doi: 10.1159/000289817Moore KL, Persaud TVN, Torchia MG. The developing human: clinically oriented embryology. 9th ed. Philadelphia: Saunders/Elsevier; 2013. ISBN: 978-1-4377-2002-0Sutherland A, Keller R, Lesko A. Convergent extension in mammalian morphogenesis. Semin Cell Dev Biol. 2020;100:199–211. doi: 10.1016/j.semcdb.2019.11.002 EDN: RSZWKPRoszko I, Sawada A, Solnica-Krezel L. Regulation of convergence and extension movements during vertebrate gastrulation by the Wnt/PCP pathway. Semin Cell Dev Biol. 2009;20(8):986–997. doi: 10.1016/j.semcdb.2009.09.004Ybot-Gonzalez P, Savery D, Gerrelli D, et al. Convergent extension, planar-cell-polarity signalling and initiation of mouse neural tube closure. Development. 2007;134(4):789–799. doi: 10.1242/dev.000380 EDN: XPWKCRSmith WC. Cellular processes of notochord formation. Adv Exp Med Biol. 2018;1029:165–177. doi: 10.1007/978-981-10-7545-2_15Yasuoka Y. Morphogenetic mechanisms forming the notochord rod: The turgor pressure-sheath strength model. Dev Growth Differ. 2020;62(6):379–390. doi: 10.1111/dgd.12665 EDN: VPMLXXEllis K, Bagwell J, Bagnat M. Notochord vacuoles are lysosome-related organelles that function in axis and spine morphogenesis. J Cell Biol. 2013;200(5):667–679. doi: 10.1083/jcb.201212095Ellis K, Hoffman BD, Bagnat M. The vacuole within: how cellular organization dictates notochord function. Bioarchitecture. 2013;3(3):64–68. doi: 10.4161/bioa.25503Shestopalov IA, Pitt CL, Chen JK. Spatiotemporal resolution of the Ntla transcriptome in axial mesoderm development. Nat Chem Biol. 2012;8(3):270–276. doi: 10.1038/nchembio.772Seleit A, Gross K, Onistschenko J, et al. Development and regeneration dynamics of the Medaka notochord. Dev Biol. 2020;463(1):11–25. doi: 10.1016/j.ydbio.2020.03.001 EDN: SWENGHBagwell J, Norman J, Ellis K, et al. Notochord vacuoles absorb compressive bone growth during zebrafish spine formation. Elife. 2020;9:e51221. doi: 10.7554/eLife.51221 EDN: QCZSGKVoigt B, Frazier K, Yazdi D, et al. A conserved regulation of cell expansion underlies notochord mechanics, spine morphogenesis, and endochondral bone lengthening. Preprint. bioRxiv. 2024:2024.08.12.607640. doi: 10.1101/2024.08.12.607640Ward L, Pang ASW, Evans SE, Stern CD. The role of the notochord in amniote vertebral column segmentation. Dev Biol. 2018;439(1):3–18. doi: 10.1016/j.ydbio.2018.04.005Lu Q, Bhattachan P, Dong B. Ascidian notochord elongation. Dev Biol. 2019;448(2):147–153. doi: 10.1016/j.ydbio.2018.11.009Dong B, Horie T, Denker E, et al. Tube formation by complex cellular processes in Ciona intestinalis notochord. Dev Biol. 2009;330(2):237–249. doi: 10.1016/j.ydbio.2009.03.015Bi J, Ge Y, Wang Z, et al. Matrix metalloproteinase Nas15 regulates the lumen formation and expansion in Ciona notochord. Front Ecol Evol. 2024;12:1385516. doi: 10.3389/fevo.2024.1385516 EDN: MKAFKFEvans AL, Faial T, Gilchrist MJ, et al. Genomic targets of Brachyury (T) in differentiating mouse embryonic stem cells. PLoS One. 2012;7(3):e33346. doi: 10.1371/journal.pone.0033346 EDN: PNAIDFCheng C, Cong Q, Liu Y, et al. Yap controls notochord formation and neural tube patterning by integrating mechanotransduction with FoxA2 and Shh expression. Sci Adv. 2023;9(24):eadf6927. doi: 10.1126/sciadv.adf6927 EDN: ZQABEGSebé-Pedrós A, Ariza-Cosano A, Weirauch MT, et al. Early evolution of the T-box transcription factor family. Proc Natl Acad Sci U S A. 2013;110(40):16050–16055. doi: 10.1073/pnas.1309748110Morley RH, Lachani K, Keefe D, et al. A gene regulatory network directed by zebrafish No tail accounts for its roles in mesoderm formation. Proc Natl Acad Sci U S A. 2009;106(10):3829–3834. doi: 10.1073/pnas.0808382106Garnett AT, Han TM, Gilchrist MJ. Identification of direct T-box target genes in the developing zebrafish mesoderm. Development. 2009;136(5):749–760. doi: 10.1242/dev.024703José-Edwards DS, Oda-Ishii I, Kugler JE, et al. Brachyury, Foxa2 and the cis-regulatory origins of the notochord. PLoS Genet. 2015;11(12):e1005730. doi: 10.1371/journal.pgen.1005730 EDN: WSQHULBalmer S, Nowotschin S, Hadjantonakis AK. Notochord morphogenesis in mice: Current understanding & open questions. Dev Dyn. 2016;245(5):547–557. doi: 10.1002/dvdy.24392Lolas M, Valenzuela PDT, Tjian R, Liu Z. Charting Brachyury-mediated developmental pathways during early mouse embryogenesis. Proc Natl Acad Sci U S A. 2014;111(12):4478–4483. doi: 10.1073/pnas.1402612111Ukita K, Hirahara S, Oshima N, et al. Wnt signaling maintains the notochord fate for progenitor cells and supports the posterior extension of the notochord. Mech Dev. 2009;126(10):791–803. doi: 10.1016/j.mod.2009.08.003Kimelman D. A novel cold-sensitive mutant of ntla reveals temporal roles of Brachyury in zebrafish. Dev Dyn. 2016;245(8):874–880. doi: 10.1002/dvdy.24417Yamanaka H, Moriguchi T, Masuyama N, et al. JNK functions in the non-canonical Wnt pathway to regulate convergent extension movements in vertebrates. EMBO Rep. 2002;3(1):69–75. doi: 10.1093/embo-reports/kvf008Choi KS, Harfe BD. Hedgehog signaling is required for formation of the notochord sheath and patterning of nuclei pulposi within the intervertebral discs. Proc Natl Acad Sci U S A. 2011;108(23):9484–9489. doi: 10.1073/pnas.1007566108Latimer AJ, Appel B. Notch signaling regulates midline cell specification and proliferation in zebrafish. Dev Biol. 2006;298(2):392–402. doi: 10.1016/j.ydbio.2006.05.039Gray SD, Dale JK. Notch signalling regulates the contribution of progenitor cells from the chick Hensen’s node to the floor plate and notochord. Development. 2010;137(4):561–568. doi: 10.1242/dev.041608Jacobs CT, Huang P. Notch signalling maintains Hedgehog responsiveness via a Gli-dependent mechanism during spinal cord patterning in zebrafish. Elife. 2019;8:e49252. doi: 10.7554/eLife.49252Wu Y, Devotta A, José-Edwards DS, et al. Xbp1 and Brachyury establish an evolutionarily conserved subcircuit of the notochord gene regulatory network. Elife. 2022;11:e73992. doi: 10.7554/eLife.73992 EDN: WFGUXETanegashima K, Zhao H, Rebbert ML, Dawid IB. Coordinated activation of the secretory pathway during notochord formation in the Xenopus embryo. Development. 2009;136(21):3543–3548. doi: 10.1242/dev.036715Garcia J, Bagwell J, Njaine B, et al. Sheath cell invasion and trans-differentiation repair mechanical damage caused by loss of caveolae in the zebrafish notochord. Curr Biol. 2017;27(13):1982–1989.e3. doi: 10.1016/j.cub.2017.05.035Lim YW, Lo HP, Ferguson C, et al. Caveolae protect notochord cells against catastrophic mechanical failure during development. Curr Biol. 2017;27(13):1968–1981.e7. doi: 10.1016/j.cub.2017.05.067Khlopin NG. General biological and experimental bases of histology. Moscow: Izdatel’stvo Akademii nauk SSSR; 1946. (In Russ.)Koehl MAR, Quillin KJ, Pell CA. Mechanical design of fiber-wound hydraulic skeletons: The stiffening and straightening of embryonic notochords. American Zoologist. 2000;40(1):28–41. doi: 10.1093/icb/40.1.28 EDN: HTETRZBocina I, Saraga-Babić M. The notochordal sheath in amphioxus--an ultrastructural and histochemical study. Coll Antropol. 2006;30(2):361–367.Munro EM, Odell G. Morphogenetic pattern formation during ascidian notochord formation is regulative and highly robust. Development. 2002;129(1):1–12. doi: 10.1242/dev.129.1.1Jiang D, Smith WC. Ascidian notochord morphogenesis. Dev Dyn. 2007;236(7):1748–1757. doi: 10.1002/dvdy.21184Lawson L, Harfe BD. Notochord to nucleus pulposus transition. Curr Osteoporos Rep. 2015;13(5):336–341. doi: 10.1007/s11914-015-0284-x EDN: EVBCDTAlkhatib B, Ban GI, Williams S, Serra R. IVD development: Nucleus pulposus development and sclerotome specification. Curr Mol Biol Rep. 2018;4(3):132–141. doi: 10.1007/s40610-018-0100-3Sakai D, Nakamura Y, Nakai T, et al. Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc. Nat Commun. 2012;3:1264. doi: 10.1038/ncomms2226Sakai D, Andersson GB. Stem cell therapy for intervertebral disc regeneration: obstacles and solutions. Nat Rev Rheumatol. 2015;11(4):243–256. doi: 10.1038/nrrheum.2015.13 EDN: USFKLZWang F, Zang C, Shi R, et al. The embryonic and evolutionary boundaries between notochord and cartilage: a new look at nucleus pulposus-specific markers. Osteoarthritis Cartilage. 2018;26(10):1274–1282. doi: 10.1016/j.joca.2018.05.022 EDN: YISYHBBach FC, Poramba-Liyanage DW, Riemers FM, et al. notochordal cell-based treatment strategies and their potential in intervertebral disc regeneration. Front Cell Dev Biol. 2022;9:780749. doi: 10.3389/fcell.2021.780749 EDN: GTARCQKorecki CL, Taboas JM, Tuan RS, Iatridis JC. Notochordal cell conditioned medium stimulates mesenchymal stem cell differentiation toward a young nucleus pulposus phenotype. Stem Cell Res Ther. 2010;1(2):18. doi: 10.1186/scrt18 EDN: BYOAKOLopez-Baez JC, Simpson DJ, LLeras Forero L, et al. Wilms Tumor 1b defines a wound-specific sheath cell subpopulation associated with notochord repair. Elife. 2018;7:e30657. doi: 10.7554/eLife.30657López-Cuevas P, Deane L, Yang Y, et al. Transformed notochordal cells trigger chronic wounds in zebrafish, destabilizing the vertebral column and bone homeostasis. Dis Model Mech. 2021;14(3):dmm047001. doi: 10.1242/dmm.047001 EDN: RFDACPRito T, Libby ARG, Demuth M, et al. Timely TGFβ signalling inhibition induces notochord. Nature. 2025;637(8046):673–682. doi: 10.1038/s41586-024-08332-w EDN: CZKKEJ