The notochord: development, disease and stem cell-based modelling

The notochord is a defining feature of chordates. 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.