The brain and spinal cord, which together form the central nervous system, begin as a simple, flat sheet of cells. This transformation into a complex tubular structure is known as neurulation, an orchestrated sequence of events that takes place very early in embryonic development. The resulting neural tube is the precursor for the entire nervous system. This developmental window is narrow, occurring primarily between the third and fourth weeks of gestation, often before a woman is aware she is pregnant.
The Step-by-Step Process of Neurulation
Neurulation begins when the notochord, a rod-like structure formed in the middle layer of the embryo, signals the overlying surface layer (ectoderm) to thicken. This signaling induces the formation of the neural plate, a flat layer of specialized cells. The formation of this plate marks the initial stage of primary neurulation, which forms the brain and most of the spinal cord.
Following the formation of the neural plate, the lateral edges begin to elevate, while the center simultaneously folds inward. This elevation and folding creates the neural groove, which runs along the midline of the developing embryo. The upwardly moving edges are called the neural folds, and their movement is driven by coordinated changes in cell shape.
The neural folds continue to move toward each other, converging above the neural groove. Fusion typically begins in the cervical (neck) region and then proceeds in a zipper-like fashion in both the cranial (head) and caudal (tail) directions. This fusion converts the neural groove into a hollow cylinder—the completed neural tube.
As the folds fuse, three distinct populations of cells are formed: the internal neural tube, the external surface ectoderm (which will become the skin), and the neural crest cells. The openings at the cranial and caudal ends of the tube are called the anterior and posterior neuropores. The anterior neuropore closes around day 25, and the posterior neuropore closes around day 28, marking the completion of primary neurulation.
The neural crest cells originate at the border between the neural plate and the surface ectoderm. They separate from the newly formed tube and migrate throughout the embryo, undergoing epithelial-to-mesenchymal transition to form a wide variety of tissues. The final step in forming the spinal cord’s lowest segments involves secondary neurulation, where a solid cord of cells forms and then hollows out to connect with the primary neural tube.
Structures That Develop From the Neural Tube
A successful closure of the neural tube results in the formation of the entire central nervous system. The cranial end of the tube undergoes rapid expansion and differentiation, forming three primary swellings known as brain vesicles: the prosencephalon (forebrain), the mesencephalon (midbrain), and the rhombencephalon (hindbrain).
The prosencephalon further divides to form structures like the cerebral hemispheres and the thalamus, which acts as a sensory relay center. The rhombencephalon differentiates into the cerebellum, which coordinates movement and balance, and brainstem components like the pons and medulla. The mesencephalon develops into the midbrain, a center for auditory and visual reflexes.
The caudal portion of the neural tube forms the spinal cord. Within the walls of the tube, cells differentiate into specialized neurons. The dorsal (back) region forms the alar plate for sensory processing, and the ventral (front) region forms the basal plate for motor control. The hollow center persists as the ventricular system in the brain and the central canal in the spinal cord, which circulate cerebrospinal fluid.
The neural crest cells contribute significantly to structures outside the central nervous system, forming many components of the peripheral nervous system. These cells differentiate into the neurons and supporting cells (glia) of the peripheral nerves, the pigment cells (melanocytes) of the skin, and the cartilage and bone of the face and skull. They also contribute to the adrenal medulla and the smooth muscle of some large blood vessels.
When Neural Tube Formation Fails
When neurulation is disrupted, it leads to neural tube defects (NTDs), which are among the most common structural birth defects. The severity and type of defect depend on where and to what extent the neural tube fails to close. These failures occur within the first month of pregnancy, before many individuals realize they are pregnant.
Anencephaly is a severe NTD resulting from the failure of the anterior neuropore to close. This condition is characterized by the absence of major portions of the brain, skull, and scalp. Infants with anencephaly are typically stillborn or die shortly after birth because the forebrain and cerebrum are missing or undeveloped.
Spina Bifida is the general term for defects caused by the failure of the posterior neuropore to close along the spine. The mildest form is Spina Bifida Occulta, where a small gap exists in the bones of the spine, but the spinal cord and nerves remain inside and are often covered by skin. This form frequently causes no symptoms and may only be marked by a tuft of hair or a dimple on the lower back.
Meningocele is a more apparent form where the protective membranes surrounding the spinal cord (meninges) push through the opening in the vertebrae, forming a sac filled with fluid. Because the spinal cord is typically not in the sac, nerve damage is usually minor, and the prognosis is favorable with surgical repair. The most severe form is Myelomeningocele, where the sac contains the meninges, fluid, spinal cord, and nerves. This open defect often results in moderate to severe disabilities, including paralysis, bowel and bladder control issues, and hydrocephalus due to nerve damage.
Critical Nutritional Requirements for Proper Closure
The risk of NTDs can be reduced through preventative measures, primarily focused on maternal nutrition during the periconceptional period. Folic acid, the synthetic form of the B-vitamin folate, is a preventative factor against these defects. Folate is involved in DNA synthesis and repair, making it important for the rapid cell division occurring during early embryogenesis.
Health organizations recommend that all women capable of becoming pregnant consume 400 micrograms (0.4 mg) of folic acid daily. Since nearly half of all pregnancies are unplanned, continuous daily supplementation is the most effective strategy. This intake should begin at least one month before conception and continue through the first two to three months of pregnancy, the window when the neural tube is forming and closing.
For women who have previously had an NTD-affected pregnancy, the risk of recurrence is higher, requiring a higher dosage. In these high-risk cases, the recommendation increases significantly to 4,000 micrograms (4 mg) of folic acid per day. This higher dosage must be started before conception and maintained through the first trimester, often taken as a separate supplement to avoid ingesting unsafe levels of other vitamins.
Beyond folic acid deficiency, other maternal factors can increase the risk of NTDs, suggesting a complex interplay of genetic and environmental influences. These factors include:
- Poorly managed maternal diabetes.
- Obesity before pregnancy.
- The use of certain antiseizure medications.
- Increased core body temperature, such as from a prolonged fever or excessive use of hot tubs.