Neurulation Steps

Why This Matters

Neurulation is the process that builds the entire central nervous system from a flat sheet of cells—it's the developmental event that transforms ectoderm into the brain and spinal cord. You're being tested on your understanding of morphogenesis, cell signaling, induction, and the molecular mechanisms that drive tissue folding and differentiation. Exam questions frequently ask you to connect specific cellular behaviors (like changes in cell shape or adhesion) to the larger structural outcomes they produce.

Don't just memorize the sequence of events—know why each step happens at the cellular level and what goes wrong when these processes fail. Neural tube defects like spina bifida appear regularly on exams as clinical correlates, and FRQs often ask you to trace how signaling from the notochord ultimately produces a functional nervous system. Understanding neurulation means understanding how cells coordinate shape changes, migration, and differentiation to build complex structures.

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Induction and Initial Patterning

The neural tube doesn't form spontaneously—it requires inductive signals from underlying tissues. The notochord and paraxial mesoderm secrete molecules that instruct overlying ectoderm to adopt a neural fate rather than becoming epidermis.

Neural Plate Formation

• Notochord-derived signals (including noggin, chordin, and follistatin) inhibit BMP signaling in overlying ectoderm, inducing neural fate
• Ectodermal thickening creates a distinct flat structure as cells become columnar and elongate perpendicular to the surface
• Molecular markers like Sox genes begin expression, distinguishing neural ectoderm from surrounding tissue destined to become skin

Regionalization of the Neural Tube

• Morphogen gradients establish anterior-posterior and dorsal-ventral axes before and during tube closure
• Sonic hedgehog (Shh) from the notochord ventralizes the neural tube, while BMPs from the roof plate dorsalize it
• Hox gene expression along the anterior-posterior axis determines which regions become forebrain, midbrain, hindbrain, and spinal cord segments

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Morphogenetic Movements: Folding and Elevation

The transformation from flat plate to closed tube requires coordinated changes in cell shape and behavior. Apical constriction, driven by actomyosin contraction, is the primary force that bends the neural plate.

Neural Plate Folding

• Apical constriction causes cells to become wedge-shaped, with narrow apical surfaces and wider basal surfaces, creating the neural groove
• Cytoskeletal rearrangements involving actin and myosin generate the contractile forces needed for bending
• Median hinge point (MHP) cells at the midline anchor to the notochord and undergo the most dramatic shape changes

Neural Fold Elevation

• Dorsolateral hinge points (DLHPs) form as additional bending sites, allowing the folds to rise toward midline
• Cell proliferation in the neural plate increases tissue mass, contributing to fold elevation
• Changes in cell adhesion help the folds separate from adjacent surface ectoderm as they elevate

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Fusion and Closure

The elevated neural folds must meet and fuse to create a continuous tube. This process requires precise coordination of cell adhesion molecules and occurs at multiple closure points simultaneously.

Neural Fold Fusion

• Cell adhesion molecule switching occurs as neural folds meet—cells downregulate E-cadherin and upregulate N-cadherin
• Cellular protrusions from opposing fold edges interdigitate and establish initial contact points
• Signaling pathways including Wnt and planar cell polarity (PCP) coordinate the fusion process across the tissue

Neural Tube Closure

• Multiple closure initiation sites exist in mammals—closure begins at several points and proceeds bidirectionally in a "zipper-like" fashion
• Neural tube defects (NTDs) result from closure failure: anencephaly (anterior failure) and spina bifida (posterior failure)
• Folic acid prevents many NTDs by supporting one-carbon metabolism essential for DNA synthesis and methylation during rapid cell division

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Neural Crest: The Fourth Germ Layer

Neural crest cells arise at the boundary between neural and non-neural ectoderm and give rise to an astonishing diversity of cell types. Their behavior exemplifies epithelial-to-mesenchymal transition (EMT), a process also critical in cancer metastasis.

Neural Crest Cell Migration

• Epithelial-to-mesenchymal transition (EMT) allows neural crest cells to delaminate from the neuroepithelium and become migratory
• Derivatives include peripheral neurons, Schwann cells, melanocytes, craniofacial cartilage and bone, and adrenal medulla cells
• Transcription factors Snail and Slug downregulate E-cadherin, enabling cells to break free and migrate along defined pathways

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Secondary Neurulation and Lumen Formation

Not all of the neural tube forms by folding—the posterior (caudal) region uses a distinct mechanism. Secondary neurulation involves cavitation of a solid cell mass rather than folding of a sheet.

Secondary Neurulation

• Mesenchymal condensation forms a solid rod of cells (the medullary cord) in the tail region of the embryo
• Cavitation creates a lumen within this solid mass, which then connects to the primary neural tube
• Caudal spinal cord and filum terminale form via this mechanism, complementing primary neurulation anteriorly

Formation of the Central Canal

• Lumen formation occurs as the neural tube undergoes cavitation and neuroepithelial cells organize around a central space
• Cerebrospinal fluid (CSF) will eventually fill this canal and the brain ventricles, providing cushioning and nutrient transport
• Ventricular zone cells lining the canal serve as neural stem cells, proliferating to generate neurons and glia

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Differentiation and Functional Organization

Once the tube is formed, neuroepithelial cells must differentiate into the diverse cell types of the nervous system. This process depends on both intrinsic transcription factor cascades and extrinsic morphogen gradients.

Differentiation of Neuroepithelium

• Neuroepithelial cells first become radial glia, which serve as both neural stem cells and scaffolds for migrating neurons
• Neurogenesis precedes gliogenesis—neurons are born first, followed by astrocytes and oligodendrocytes
• Proneural genes (like Neurogenin and Mash1) promote neuronal fate, while other factors promote glial differentiation

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Quick Reference Table

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Self-Check Questions

1. Which two steps of neurulation both depend on the formation of hinge points, and what cellular mechanism drives bending at these sites?

2. Compare and contrast primary and secondary neurulation—where in the embryo does each occur, and what is the key morphogenetic difference between them?

3. If an embryo has a mutation that prevents N-cadherin expression, which step of neurulation would most likely fail, and why?

4. Neural crest cells and neural tube cells both derive from ectoderm. What process allows neural crest cells to migrate while neural tube cells remain in place, and what molecular changes characterize this transition?

5. An FRQ asks you to explain how a single signaling molecule (Shh) contributes to multiple aspects of neural tube development. Which steps would you discuss, and what role does Shh play in each?