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It acts as mechanical support and a source of signals to surrounding tissues during development. In mammals, notochord-derived cells persist within intervertebral discs, where they form the nucleus pulposus, the cartilage in between vertebrae units that provides the spine with flexibility. Here, we synthesise developmental knowledge with recent advances in notochord biology and insights from single-cell molecular approaches. We discuss the developmental processes from notochord initiation during gastrulation through to disc formation, highlighting signalling pathways that govern axial mesoderm specification and notochordal lineage commitment. Knowledge gained from in vivo studies has guided the development of pluripotent stem cell-based models in mice and humans, including monolayer and micropatterned systems and 3D organoids. These models recapitulate key developmental aspects of notochord formation and pave the way for disease modelling and regenerative applications. We discuss their relevance to the study of developmental disorders arising from notochord dysfunction and notochordal cell roles in disc homeostasis. Finally, we outline remaining questions and examine how developmental insights and stem cell innovations can advance our understanding of tissue formation, function and homeostasis while fostering the integration of basic mechanistic insights with translational applications.<\/jats:p>","DOI":"10.1242\/dev.205337","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T11:58:41Z","timestamp":1781524721000},"source":"Crossref","is-referenced-by-count":2,"title":["The notochord: development, disease and stem cell-based modelling"],"prefix":"10.1242","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0069-9428","authenticated-orcid":false,"given":"Julie","family":"Warin","sequence":"first","affiliation":[{"name":"Nantes Universit\u00e9, Oniris, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229 1 , F-44000 Nantes ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiago","family":"Rito","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences 2 , Li Ka Shing Faculty of Medicine , , Hong Kong SAR ,","place":["China"]},{"name":"The University of Hong Kong 2 , Li Ka Shing Faculty of Medicine , , Hong Kong SAR ,","place":["China"]},{"name":"The Francis Crick Institute 3 , 1 Midland Road, London NW1 1AT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Briscoe","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute 3 , 1 Midland Road, London NW1 1AT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Blin","sequence":"additional","affiliation":[{"name":"Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh 4 , Edinburgh EH16 4UU ,","place":["UK"]},{"name":"Institute for Stem Cell Research, School of Biological Sciences, The University of Edinburgh 5 , Edinburgh EH16 4UU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8820-0407","authenticated-orcid":false,"given":"Anne","family":"Camus","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, Oniris, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229 1 , F-44000 Nantes ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"2026061511564146200_DEV205337C1","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1101\/gad.303504","article-title":"The mouse homeobox gene Not is required for caudal notochord development and affected by the truncate mutation","volume":"18","author":"Abdelkhalek","year":"2004","journal-title":"Genes Dev."},{"key":"2026061511564146200_DEV205337C2","doi-asserted-by":"publisher","first-page":"eabl3674","DOI":"10.1126\/sciadv.abl3674","article-title":"Personalized chordoma organoids for drug discovery studies","volume":"8","author":"Al Shihabi","year":"2022","journal-title":"Sci. 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