Development of the Brain, Spinal Cord, and Face

Neurulation and Neural Crest Migration

The development of the brain is a specific part of gastrulation, called neurulation, that creates the cells of the nervous system.

Neurulation

Day 16 after fertilization → embryonal cells belong to 1 of 3 germ cell layers:

• Ectoderm
  • Differentiates into the neuroectoderm, creating the neural plate
  • Cell replication in the neural plate gives rise to 2 ridges (neural crests).
  • The depression between the crests is known as the neural fold.
• Mesoderm
  • Differentiates and transforms in a tube structure called the notochord.
  • The notochord signals the neural fold to enlarge on either side of the neural groove, creating the neural tube.
• Endoderm

Neural crest cell migration

Neuroectoderm cells migrate in waves from the neural crests to create peripheral nervous system structures:

• The 1st wave of migration creates:
  • Sympathetic ganglia
  • Parasympathetic ganglia
  • Chromaffin cells (sympathetic ganglia migrated into the adrenal medulla)
• The 2nd wave of migration creates:
  • Posterior root ganglia
  • Schwann cells
  • Satellite cells
• The 3rd wave of migration creates:
  • Melanocytes
• Neural crest cells in the head and neck also form different structures:
  • Make up secondary ganglia of cranial nerves 5, 7, 9, and 10
  • Migrate into the pharyngeal arches of the head, neck, and face to create mesenchyme, which contributes to bone and connective tissue

Mnemonics

• To quickly recall that each Schwann cell myelinates only 1 axon of the peripheral nervous system, remember: “Schwone” = 1 axon.
• To quickly recall where oligodendrocyte and Schwann cells are located, remember: COPS: CNS = Oligodendrocyte; PNS = Schwann cells.

Neural Tube

Primary vesicles

The neural tube develops 3 bulges (primary brain vesicles) at the cranial end:

1. Prosencephalon (forebrain) splits, giving rise to:
   • The telencephalon, which becomes the cerebral cortex. This portion of the neural canal becomes the lateral ventricles and 3rd ventricle.
   • The diencephalon, which becomes the thalamus, hypothalamus, and pineal gland
2. Mesencephalon (midbrain): also contains the cerebral aqueduct
3. Rhombencephalon (hindbrain) splits to become:
   • The metencephalon, which becomes the pons and cerebellum
   • The myelencephalon, which becomes the medulla oblongata
   • The remnant of the neural canal present around the metencephalon and myelencephalon, which becomes the 4th ventricle

Cerebrospinal fluid (CSF) circulatory system

• Ependymal cells:
  • Line the central canal and the core of the neural tube
  • In lateral, 3rd, and 4th ventricles, ependymal cells become the choroid plexus.
• Choroid plexus: filters blood and releases CSF into the ventricular system

Flexion of the neural tube

The neural tube develops a series of bends in the sagittal plane:

• At 3-vesicle stage:
  • Cervical flexure: between spinal cord and rhombencephalon
  • Cephalic flexure: between prosencephalon and mesencephalon
• As the neural tube develops further: pontine flexure (between myelencephalon and metencephalon)

Development of the Spinal Cord and Brainstem

Spine

As the cephalic portion of the neural tube becomes the brain, the rest becomes the spinal cord.

• Proliferation of neuroepithelial cells 
  • As they push outward, intermediate and marginal zones are created.
  • Marginal zone: comes in contact with sclerotomal mesenchyme that will form the meninges
  • Intermediate and marginal zones fill the space inside the neural canal.
  • The cells in the marginal and intermediate zones will differentiate into neurons. 
• The neuroepithelial tissue of the spine has a regional specialization:
  • Alar plate (sensory): 
    • Axons extend to the brain.
    • Neurons in dorsal root ganglia (originally from neural crest cells) extend to the skin and back to the Alar plate.
  • Basal plate (motor): Neurons innervate myotome.
  • Sulcus limitans: separates alar plate from the basal plate
• Top and bottom of the neural tube are closed by the roof plate and floor plate.
• Central canal at the core of neural tube: lined by ependymal cells
• The spinal cord fills the bony spine as the fetus develops.
  • Week 8: Spinal cord extends along the entire length of the vertebral column.
  • Inferior end reaches:
    • L3 level at birth
    • L1 level in adulthood
  • Spinal nerve roots that exit below L1–L3 create the cauda equina
  • Conus medullaris: tapered end of the spinal cord
  • Filum terminale: connects conus medullaris to the coccygeal vertebra

Brainstem

The brainstem resembles the spinal cord in embryological organization. The basal plate gives rise to motor nuclei, while the alar plate gives rise to sensory nuclei.

• Caudal medulla
  • Sensory nuclei are dorsal.
  • Motor nuclei are ventral.
• Cranial medulla
  • Roof plate is more opened up (“open book” appearance).
  • The basal plate is more medially located.
  • The alar plate is more laterally located.
  • Some sensory neurons migrate anteriorly to form the olivary nucleus later in development.
• Pons
  • Alar plate migrates to take a spot anterior to the basal plate and gives rise to the pontine nuclei.
  • Basal plate is now more posterior, but still gives rise to all the motor nuclei.
  • Cerebellum develops directly posterior to the pons from neuroepithelial cells.

Development of the Cerebral Cortex

The cortex develops from the telencephalon.

• The neural canal at this level develops into the left and right ventricles.
• Interventricular foramen: connects lateral ventricles to the 3rd ventricle
• The development of lobes of the brain occurs from the ventricles outward:
  • Neuron precursor cells near the ventricles replicate rapidly.
  • Glial cells extend radial processes to provide a pathway for the neurons.
  • Neuroepithelial cells migrate laterally, passing through subventricular zone → intermediate zone → cortical plate → marginal zone
  • Different kinds of neurons stop at different points, giving rise to specialized layers.
• 6 months: Distinctive lobes start to appear.
• Corpus callosum: 
  • Becomes more defined as neurons from 1 cortex migrate to the other
  • Nervous structure that allows 1 side of the brain to communicate with another side
• Gyri and sulci are not evident until near term.
• 9 months: Brain looks like a smaller version of the adult brain.

Development of the Face

• End of the 4th week: 1st facial structures are visible.
  • Centrally: stomodeum (early mouth)
  • Inferiorly: mandibular prominence
  • Laterally: 2 maxillary prominences
  • Superiorly: frontonasal prominence with nasal placodes
• 5th week: Nasal placodes deepen into nasal pits surrounded by nasal prominences.
• 6th and 7th weeks:
  • Mandibular prominences fuse → jaw formed
  • Eyes are visible on the lateral side of the face (as frontonasal prominence narrows, eyes move medially).
  • Nasolacrimal groove forms: junction between frontonasal prominence and maxillary prominence, future nasolacrimal duct
  • Medial nasal prominences:
    • Grow together and fuse at the midline → stretch inferiorly
    • Fuse with maxillary prominence → form the upper lip
  • Medial and lateral nasal prominences: fuse with the maxillary prominence → form cheek and upper lip
  • Frontonasal prominence → becomes the forehead, nose, and philtrum
• Maxillary prominence → cheek
• Mandibular prominence → mandible and area anterior to the ear

Clinical Relevance

The following are pathological conditions that can arise as a result of errors in the development of the brain, spinal cord, and face:

• Hydrocephalus: blockage of the ventricular system that causes swelling and pressure exerted on the brain. In adults, the skull is already developed, so accumulated fluid presses on the brain. In neonates, as bones have not yet completely ossified, the head circumference increases. May be caused congenitally by cerebral aqueduct stenosis.
• Posterior fossa malformations (Arnold-Chiari malformations (CM)): Chiari I malformation is a congenital disorder associated with ectopic cerebellar tonsils located inferior to the foramen magnum. Children are usually asymptomatic. Chiari II malformation is caused by herniation of the cerebellar tonsils, as well as vermis, through the foramen magnum. Chiari II leads to non-communicating hydrocephalus.
• Frontonasal dysplasia (cleft lip and cleft palate): Sonic hedgehog overactivity causes accumulation of excessive tissue in the frontonasal prominence area, resulting in a broad nose and widely separated eyes (hypertelorism). This disorder may also cause cleft nose and midline cleft lip due to the failure to fuse medial nasal prominences.
• Holoprosencephaly: a disorder caused by decreased activity of the sonic hedgehog gene, resulting in narrowing of the face. More severe cases involve failure of the right and left cerebral cortexes to fully separate, as well as cyclopia. 
• Neural tube defects: 1 of the most common congenital CNS malformations. The defects develop between the 3rd and 4th week of gestation and are often caused by folic acid deficiency. The deficiency results in improper closure of the neural plate in the embryo, mainly at the caudal or cranial ends, giving rise to anencephaly.