Neurulation

Primary neurulation is the dominant mode in the cranial and upper spinal regions of amniotes. It begins with the elongation of the neural plate, a thickened ectodermal layer, under the influence of the underlying notochord and prechordal mesoderm.¹ The plate then bends at hinge points—the median hinge point over the notochord and paired dorsolateral hinge points—driven by cell shape changes, particularly apical constriction of neuroepithelial cells.³ Elevation of the neural folds brings the edges together, and fusion occurs at the dorsal midline, starting at the future cervical region and proceeding both cranially and caudally. The fusion creates the neural tube, which then separates from the overlying ectoderm.

Secondary neurulation forms the neural tube by cavitation of a solid cord of cells, rather than by folding. In humans and other amniotes, this mode occurs in the tailbud region, giving rise to the caudal spinal cord.⁴ The process involves the condensation of mesenchymal cells into a medullary cord, which then forms a central canal. In contrast, in fish and amphibians, secondary neurulation is the primary mechanism for the entire spinal cord, while primary neurulation is limited to the brain. Birds and mammals exhibit both modes, with the transition point varying by species; in humans, the transition is around the level of the second sacral vertebra.

Neurulation is orchestrated by a complex network of signaling molecules. The notochord secretes Sonic hedgehog (SHH), which establishes the ventral identity of the neural tube and induces the floor plate.⁵ Bone morphogenetic proteins (BMPs) from the ectoderm and dorsal neural tube pattern the dorsal region, while Wnt and FGF signals regulate proliferation and differentiation. Transcription factors such as Pax3, Pax6, and Sox2 are essential for neural plate specification. Disruption of these pathways, either by genetic mutations or environmental factors like folate deficiency, can lead to failed closure and neural tube defects.² The planar cell polarity (PCP) pathway is also critical for convergent extension movements that narrow and elongate the neural plate.

Neurulation is not a single continuous event but occurs at multiple closure sites. In humans, at least two, and possibly five, distinct fusion points exist, with the anterior neuropore closing around day 24 and the posterior neuropore around day 26.⁶ Failure of the anterior neuropore leads to anencephaly, while posterior failure leads to spina bifida. A lesser-known fact is that the neural tube transiently opens to the amniotic fluid via neuropores, and their closure is regulated by apoptosis at the fusion edges. Additionally, the process is influenced by mechanical forces, such as actin-myosin contraction, and by the stiffness of the surrounding extracellular matrix. In some species, like the chick, the neural tube forms by a 'zippering' mechanism that is sensitive to temperature, which has been used experimentally to study closure dynamics.

Neural plate

A thickened, flat layer of ectoderm that gives rise to the neural tube.

Notochord

A rod-like mesodermal structure that induces the overlying ectoderm to form the neural plate.

Apical constriction

A cell shape change where the apical surface narrows, driving tissue bending.

Neural tube defect

A birth defect resulting from incomplete closure of the neural tube, such as spina bifida.

Neuropore

An opening at the cranial or caudal end of the neural tube before closure is complete.