Step 1 · Anatomy & Embryology

Neural Tube & CNS Embryology

Name: Neural Tube & CNS Embryology
Creator: Veli Bakalov, MD

How the tube closes, what happens when it does not, and the crest cells that wander everywhere

Anatomy & Embryology·Embryology·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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The notochord induces the neural plate → folds → tube, patterns the ventral tube via SHH, and persists as the nucleus pulposus.
The neural tube closes in week 4: rostral neuropore about day 25, caudal neuropore about day 28.
NTD risk: folate deficiency, valproate or carbamazepine, maternal diabetes and obesity; prevent with folic acid 0.4 mg/day (4 mg/day after a prior affected pregnancy).
Open NTDs raise maternal serum and amniotic AFP; amniotic acetylcholinesterase confirms an open defect; spina bifida occulta has normal AFP.
Anencephaly = failed rostral neuropore closure: markedly high AFP, polyhydramnios from impaired swallowing, incompatible with life.
Alar plate (dorsal) = sensory; basal plate (ventral) = motor; the sulcus limitans divides them.
Holoprosencephaly = failed forebrain cleavage from SHH mutations; trisomy 13 and fetal alcohol syndrome; cyclopia to single central incisor.
Chiari II = vermis, tonsils, and medulla herniation with lumbar myelomeningocele and hydrocephalus; Chiari I = tonsils only, adults, syringomyelia; Dandy-Walker = vermis agenesis + cystic 4th ventricle.
Neural crest forms ganglia, Schwann cells, adrenal medulla, melanocytes, C cells, enterochromaffin cells, leptomeninges, the aorticopulmonary septum, skull bones, and odontoblasts.

Neurulation and the organization of the tube

Induction. The notochord induces the overlying ectoderm to become neuroectoderm (by blocking BMP signaling); its sonic hedgehog (SHH) then patterns the ventral tube (floor and basal plates). The notochord itself persists in the adult only as the nucleus pulposus of the intervertebral disc.

NotochordInduces the overlying ectoderm; its SHH later patterns the ventral tube.
Neural plateThickened ectoderm over the notochord.
Neural foldsThe edges elevate; neural crest cells detach from the fold crests.
Neural tubeBecomes the brain and spinal cord (the CNS).

Three ectodermal fates. Neuroectoderm forms CNS neurons, ependyma, astrocytes, and oligodendrocytes (and the posterior pituitary); neural crest forms the peripheral nervous system and many non-neural tissues; surface ectoderm forms the epidermis (and the anterior pituitary via Rathke pouch). Microglia are the exception in the CNS: they are mesoderm-derived.

Closure timing. The tube zips shut during week 4: the anterior (rostral) neuropore closes around day 25 and the posterior (caudal) neuropore around day 28. Failure of either produces a neural tube defect, often before the pregnancy is recognized, which is why folate must be started before conception.

Alar and basal plates. The dorsal alar plate becomes sensory (afferent) neurons and the ventral basal plate becomes motor neurons, separated by the sulcus limitans. This mirrors the adult spinal cord, with sensory dorsal horns and motor ventral horns.

Brain vesicles and forebrain cleavage

Three vesicles become five

Secondary vesicle (primary)	Adult derivatives	Cavity
Telencephalon (prosencephalon)	Cerebral hemispheres	Lateral ventricles
Diencephalon (prosencephalon)	Thalamus, hypothalamus	3rd ventricle
Mesencephalon	Midbrain	Cerebral aqueduct
Metencephalon (rhombencephalon)	Pons, cerebellum	4th ventricle (upper part)
Myelencephalon (rhombencephalon)	Medulla	4th ventricle (lower part)

The prosencephalon and rhombencephalon each split in two; the mesencephalon does not divide.

Holoprosencephaly. The prosencephalon fails to cleave into two hemispheres, most often from mutations in the SHH pathway; it is associated with trisomy 13 (Patau syndrome) and fetal alcohol syndrome. Findings form a midline spectrum: a monoventricle and fused hemispheres, cleft lip and palate, and facial anomalies that range from a single central maxillary incisor in mild forms to cyclopia in severe forms.

Neural tube defects

Risk factors. Periconceptional folate deficiency; folate-antagonist antiepileptics (valproate, carbamazepine); and maternal diabetes and obesity. Prevention is folic acid 0.4 mg/day for all women who could become pregnant, or 4 mg/day after a previously affected pregnancy.

Markers. Open defects leak fetal proteins, so maternal serum and amniotic alpha-fetoprotein (AFP) rise. Amniotic acetylcholinesterase (AChE), which leaks from exposed neural tissue, confirms an open defect and is more specific than AFP. Skin-covered defects such as spina bifida occulta leave AFP normal.

Neural tube defect spectrum

Defect	What fails or herniates	AFP	Clues
Spina bifida occulta	Vertebral arch fails to fuse; dura intact	Normal	Tuft of hair or dimple over the lower spine
Meningocele	Meninges herniate	Raised if open	Usually no deficits
Myelomeningocele	Meninges plus spinal cord herniate	Raised	Neurologic deficits; Chiari II
Myeloschisis	Exposed, unfused neural tissue	Raised	Most severe spinal form
Anencephaly	Rostral neuropore fails to close	Markedly raised	Absent forebrain and vault, frog-like face, polyhydramnios

Anencephaly. Without a forebrain and cranial vault the fetus cannot swallow normally, so amniotic fluid accumulates (polyhydramnios). It is incompatible with life, and folate supplementation prevents it.

Posterior fossa and cord malformations

Chiari I, Chiari II, and Dandy-Walker

Feature	Chiari I	Chiari II	Dandy-Walker
Anatomy	Cerebellar tonsils more than 3 to 5 mm below the foramen magnum	Vermis, tonsils, and medulla herniate through the foramen magnum	Vermis agenesis, cystic dilation of the 4th ventricle, enlarged posterior fossa
Timing	Often silent until adulthood (headache, cerebellar signs)	Infancy	Infancy
Associations	Syringomyelia	Lumbar myelomeningocele, obstructive hydrocephalus, syringomyelia	Hydrocephalus

Syringomyelia. A fluid-filled cavity in the central cord, usually at C8 to T1. It first damages spinothalamic fibers crossing in the anterior white commissure, producing bilateral cape-like loss of pain and temperature over the shoulders and arms with preserved light touch and proprioception (dorsal columns). As it expands it can involve the anterior horns (wasting of the intrinsic hand muscles) and lateral corticospinal tracts (spasticity below the lesion). Chiari I is the classic association.

Neural crest derivatives

Migratory cells. Neural crest cells detach from the folds as the tube closes and migrate widely. Their derivatives, and the diseases that arise from them:

Dorsal root and autonomic ganglia; Schwann cells
Adrenal medulla chromaffin cells: pheochromocytoma and neuroblastoma
Melanocytes: melanoma
Parafollicular (C) cells of the thyroid: medullary thyroid carcinoma
Enterochromaffin cells: carcinoid tumors
Pia and arachnoid (leptomeninges)
Aorticopulmonary septum: abnormal crest migration underlies conotruncal defects (persistent truncus arteriosus, tetralogy of Fallot, transposition)
Skull bones and odontoblasts

Hirschsprung disease is failed neural crest migration to the distal colon, leaving an aganglionic segment. The adrenal cortex, by contrast, is mesoderm, so a catecholamine-secreting adrenal tumor is a crest tumor while a cortisol-secreting one is not.