The notochord is a flexible, rod-shaped structure that forms in the first few weeks of human embryonic development, running along the midline of the body where the spine will eventually be. It serves as the embryo’s first skeletal support and sends chemical signals that help pattern the surrounding tissues, including the spinal cord and the vertebrae. In adults, the notochord itself is gone, but its remnants persist inside each intervertebral disc as the soft, gel-like core known as the nucleus pulposus. That transformation from a whole-body scaffold to scattered pockets of tissue is more interesting than it sounds, and it has real consequences for back pain, rare cancers, and even potential therapies.
How the Notochord Appears in the Embryo
The notochord begins forming remarkably early. Around day 17 to 19 of development, a cluster of cells called the notochordal process appears as an organized accumulation of cells just ahead of the region where gastrulation is happening, the zone where the embryo’s three fundamental cell layers are being established.1PLoS ONE. The development of the human notochord Over the following days, this structure elongates and solidifies into a definitive notochord, a rod of cells stretching from roughly the base of the developing brain to the tail end of the embryo. It sits directly beneath the developing neural tube and above the gut, and it is the first structure to give the embryo a recognizable head-to-tail axis.
The notochord arises from the mesoderm, the middle layer of the embryo that also gives rise to muscle, bone, and the circulatory system. Its position along the midline is no accident. It acts as a kind of organizing rail, and surrounding tissues take their developmental cues partly from their distance from it.
The Notochord as a Signaling Center
If the notochord were only a structural rod, it would still be important. But its signaling role is arguably more consequential. The notochord secretes proteins that instruct nearby cells what to become, and one of the most critical of these is Sonic hedgehog, usually abbreviated Shh. This protein diffuses outward from the notochord into the surrounding tissues and helps determine cell fate in the developing spinal cord and the blocks of tissue (somites) flanking it.2PubMed Central. The notochord: structure and functions
In the neural tube, the precursor to the brain and spinal cord, Shh from the notochord helps establish a gradient that determines which neurons form where. Motor neurons, for example, develop on the side of the neural tube closest to the notochord, where Shh concentration is highest. Experiments in chick embryos have shown that when Shh released from the notochord is blocked from reaching the neural tube, the number of motor neurons drops by about 40%.3PubMed Central. Neural tube development depends on notochord-derived sonic hedgehog released into the sclerotome The same signal also influences muscle development in nearby tissue.
This dual role as both mechanical scaffolding and chemical broadcaster makes the notochord unusually important for its size. Remove it or disable its signaling and you get catastrophic developmental defects in the spine, the spinal cord, and the surrounding musculature.
What the Notochord Becomes in Adults
As the vertebral column forms around the notochord during fetal development, the notochord does not simply die off. Instead, it gets squeezed and incorporated. In the regions where vertebral bodies form, the notochord is largely eliminated: the expanding bone and cartilage compress it out of existence. But between the vertebrae, inside the developing intervertebral discs, sections of the notochord persist and become the nucleus pulposus, the gel-like center of each disc.4PubMed Central. Notochordal cells in the adult intervertebral disc: new perspective on an old question
The nucleus pulposus is surrounded by a tougher ring of fibrous tissue called the annulus fibrosus. Together, they form the intervertebral disc, which absorbs shock and allows flexibility between the vertebrae. In young people, the nucleus pulposus is soft, hydrated, and rich in cells that still carry notochordal markers. Over time, the character of this tissue changes considerably.
The Gradual Loss of Notochordal Cells
One of the more striking aspects of the notochord’s afterlife is how its cellular signature fades with age. Studies of human intervertebral discs across different age groups have tracked the presence of cells that still express notochordal markers. In fetal through adolescent discs, roughly 80% contain abundant cells with notochordal labeling. In young adults up to age 30, the figure is even higher. But in people over 30, the picture changes sharply: only about a quarter of discs in the 31-to-60 range still contain a few positively labeled cells, and in elderly discs the proportion is similarly low.5PubMed Central. Immunohistochemical identification of notochordal markers in cells in the aging human lumbar intervertebral disc
Separate research has identified specific molecular markers, including the transcription factor Brachyury T and certain neuronal-related proteins, that are present in juvenile nucleus pulposus tissue but absent in adult tissue.6PubMed Central. Identifying molecular phenotype of nucleus pulposus cells in human intervertebral disc with aging and degeneration In other words, the cells that populate the center of your discs gradually lose their notochordal identity as you age. They shift toward a more generic cartilage-cell appearance, and this transition seems to be connected to disc degeneration.
Why Losing Notochordal Cells May Matter for Your Back
The disappearance of notochordal cells is not just a curiosity of developmental biology; it may help explain why intervertebral discs deteriorate with age. Laboratory studies have shown that factors secreted by notochordal cells actively protect other disc cells from breaking down and dying. Specifically, these secreted factors suppress cell death by inhibiting certain enzymes involved in programmed cell death (caspases) and by boosting genes that support the structural matrix of the disc.7PubMed Central. Notochordal cells protect nucleus pulposus cells from degradation and apoptosis: implications for the mechanisms of intervertebral disc degeneration
Once those notochordal cells dwindle, the disc loses a source of protective and regenerative signals. The nucleus pulposus becomes drier and more fibrous, loses its ability to absorb compressive forces as effectively, and becomes more vulnerable to tearing. This process is essentially what clinicians mean when they talk about degenerative disc disease, a major contributor to chronic low back pain. The pattern is consistent with what the age-tracking studies show: as notochordal cells drop off, disc quality declines.
This understanding has led researchers to explore whether notochordal cells or their secretions could be used therapeutically. Early-stage work suggests that notochordal cells and the molecules they release have anti-inflammatory properties and can stimulate the remaining disc cells to proliferate and rebuild the disc’s structural matrix.8PubMed Central. Notochordal cells: A potential therapeutic option for intervertebral disc degeneration This is still far from being a clinical treatment, but it represents an approach that targets the root biology of disc degeneration rather than just managing pain.
Benign Notochordal Remnants Along the Spine
The notochord does not always retreat cleanly into the intervertebral discs. Small nests of notochordal cells sometimes persist in other locations along the craniospinal axis, from the base of the skull to the tailbone. The most well-known example is ecchordosis physaliphora, a benign remnant typically found at the back of the clivus, a bone at the base of the skull. These tiny lesions have a low growth rate, do not invade bone, and almost never cause symptoms.9American Journal of Neuroradiology. Ecchordosis Physaliphora: Does It Even Exist? They are usually discovered incidentally on brain MRI scans done for other reasons.
Another oddity that occasionally shows up on imaging is a persistent notochordal canal, a small channel running through one or more vertebral bodies that represents a tract where the notochord once passed. This can mimic the appearance of a compression fracture on plain X-rays, which sometimes leads to unnecessary alarm. CT and MRI can usually resolve the confusion and confirm the benign nature of the finding.10Medical Science Monitor. Persistent notochordal canal imitating compression fracture – plain film, CT and MR appearance
Both of these findings are reminders that the notochord’s footprint in the adult body extends beyond the intervertebral discs, even if most of these traces are harmless.
Chordoma, the Rare Cancer of Notochord Origin
Not all notochordal remnants stay benign. Chordoma is a rare, slow-growing but aggressive cancer that arises from leftover notochordal cells.11PubMed Central. Chordoma: an update on the pathophysiology and molecular mechanisms It tends to occur at the two ends of the original notochord’s range: the clivus at the base of the skull and the sacrum at the base of the spine. Chordomas share histological features and gene expression patterns with the notochord, and they are thought to develop from the same isolated embryonic notochord cells that give rise to benign remnants like ecchordosis physaliphora.12PubMed Central. Proposed Diagnostic Criteria, Classification Schema, and Review of Literature of Notochord-Derived Ecchordosis Physaliphora
In mouse studies, researchers have identified rare isolated embryonic notochord cells that remain in the vertebral column after development and resemble what in humans have been proposed as the precursors to chordoma.13PubMed Central. Identification of nucleus pulposus precursor cells and notochordal remnants in the mouse: implications for disk degeneration and chordoma formation The transition from a harmless remnant to a malignant tumor is not well understood, but it likely involves the accumulation of genetic changes in cells that were never supposed to persist.
Brachyury as a Molecular Fingerprint
One of the most useful discoveries in chordoma research has been the identification of the transcription factor Brachyury as a specific biomarker. Brachyury is a protein that plays a central role in notochord formation during embryonic development. In adults, it is essentially silent in normal tissues. But in chordomas, Brachyury is expressed at high levels. A landmark study tested a panel of over 300 tumors of other types, including 163 cartilage-related tumors that can look similar to chordoma under the microscope, and found Brachyury expression exclusively in chordomas, where all 53 tested samples were positive.14PubMed. Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas
This has practical diagnostic value. Chordomas can be difficult to distinguish from certain cartilage tumors on biopsy alone, and the distinction matters because treatment differs. A Brachyury stain can now resolve the question definitively. Beyond diagnostics, the finding reinforces the direct developmental lineage from embryonic notochord to chordoma. Brachyury is not just a marker; it is actively involved in notochord gene regulation throughout chordate evolution.15PubMed Central. From notochord formation to hereditary chordoma: the many roles of Brachyury
The Notochord in Evolutionary Context
The notochord is not a human quirk. It is one of the defining features of the entire phylum Chordata, which includes all vertebrates plus some invertebrate relatives like lancelets and tunicates.16PubMed Central. Evolution of the notochord In lancelets, the notochord persists throughout adult life as the main body support; these animals never develop a vertebral column. In tunicates, it appears briefly in the larval tail and is lost at metamorphosis. Only in vertebrates does the notochord get replaced by a bony or cartilaginous spine while leaving its remnants in the disc centers.
The notochord is considered one of the major evolutionary innovations of our lineage, though researchers debate whether structures resembling it might also exist in some non-chordate animals.17PubMed. Animal evolution: stiff or squishy notochord origins? Either way, its mechanical and signaling functions appear to be ancient. The gene Brachyury, for instance, drives notochord development in organisms as distantly related as sea squirts and mammals, and the regulatory circuitry controlling its expression in the notochord has been traced back to the last common ancestor of jawed vertebrates.18Nature Communications. Conserved enhancers control notochord expression of vertebrate Brachyury
Work in the sea squirt Ciona has mapped out in detail how Brachyury and another transcription factor, Foxa2, coordinate the activation of the notochord gene regulatory network, providing a high-resolution picture of how this ancient structure is built at the molecular level.19PubMed Central. Cis-regulatory interfaces reveal the molecular mechanisms underlying the notochord gene regulatory network of Ciona These conserved gene networks underscore that the notochord is not some dispensable scaffold humans have outgrown. It is a deeply embedded piece of the developmental program, one whose echoes persist in our disc biology and whose malfunction can still cause disease decades after the original structure has dissolved.
What Animal Studies Reveal About Notochord Mechanics
Much of what we know about how the notochord works mechanically comes from zebrafish, where the structure is large, accessible, and persists longer than in mammals. In zebrafish, notochord cells develop large fluid-filled vacuoles that expand and merge, generating hydrostatic pressure inside the notochord sheath. This internal pressure acts like an inflatable splint, stiffening the body axis and, later in development, providing a scaffold that guides symmetrical vertebral bone growth.20eLife. Notochord vacuoles absorb compressive bone growth during zebrafish spine formation
When this vacuole inflation process fails, the consequences are dramatic. Zebrafish mutants with defective notochord vacuoles lack sufficient internal pressure to support normal vertebral bone deposition and end up with misshapen vertebrae and scoliosis in adulthood.21PubMed Central. A conserved regulation of cell expansion underlies notochord mechanics, spine morphogenesis, and endochondral bone lengthening The mechanism that controls cell expansion in these notochord cells appears to be conserved across vertebrates, hinting that similar hydraulic principles were at work in the human notochord during the brief window when it served as the embryo’s primary support structure.
These findings from fish give researchers a way to study notochord biology that would be impossible in humans, where the structure forms and transforms within the first few weeks of embryonic life. They also reinforce the idea that the notochord is not a passive rod but an actively pressurized, mechanically sophisticated structure whose engineering principles continue to influence vertebral development even as the notochord itself is being replaced by bone.
Brachyury and Xbp1 in the Notochord Gene Circuit
The molecular machinery that builds a notochord is remarkably well conserved. Two transcription factors, Brachyury and Xbp1, form a cross-regulatory circuit: each influences the expression of the other, and together they activate downstream genes needed for notochord structure and function. This relationship has been demonstrated in both the sea squirt Ciona and the frog Xenopus, suggesting the circuit was present in the common ancestor of all chordates and has been maintained for hundreds of millions of years.22PubMed Central. Xbp1 and Brachyury establish an evolutionarily conserved subcircuit of the notochord gene regulatory network
Xbp1 is especially interesting because it is better known for its role in managing cellular stress responses, particularly in cells that produce and secrete large amounts of protein. Its involvement in the notochord makes sense once you consider that notochord cells secrete substantial quantities of extracellular matrix components and signaling molecules. The co-option of a stress-management gene into a structural-development role illustrates how evolution repurposes existing molecular tools rather than inventing new ones from scratch. For researchers studying disc degeneration and chordoma, these gene networks offer potential intervention points: if you understand how notochordal identity is maintained and lost at the molecular level, you may eventually learn how to preserve it in aging discs or shut it down in tumors that should never have reactivated it.