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
Neurulation: the differentiation and growth of the neural plate into the neural tube during the first trimester of gestation
Image by Lecturio.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
During the embryonic development of the central nervous system (CNS), neuroectodermal cells migrate from the neural crests in sequential waves to form specialized structures of the peripheral nervous system, including sympathetic and parasympathetic ganglia, chromaffin cells, and Schwann cells.
Image by Lecturio.
Neural crest cells arise from the edges of the neural plates that fold to form the neural tube. The neural tube gives rise to the CNS, whereas neural crest cells migrate and proliferate around the developing embryo to give rise to pigment cells, autonomic and sensory nerve cells, Schwann cells, and endocrine cells (chromaffin cells in the medulla).
Image by Lecturio.
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:
- 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
- Mesencephalon (midbrain): also contains the cerebral aqueduct
- 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
| Neural tube | Primary vesicle stage | Secondary vesicle stage | Adult structures | Ventricles |
|---|---|---|---|---|
| Anterior neural tube | Prosencephalon | Telencephalon | Cerebrum | Lateral ventricles |
| Anterior neural tube | Prosencephalon | Diencephalon | Diencephalon | 3rd ventricle |
| Anterior neural tube | Mesencephalon | Mesencephalon | Midbrain | Cerebral aqueduct |
| Anterior neural tube | Rhombencephalon | Metencephalon | Pons cerebellum | 4th ventricle |
| Anterior neural tube | Rhombencephalon | Myelencephalon | Medulla | 4th ventricle |
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)
The prosencephalon, mesencephalon, and rhombencephalon form 5 secondary brain vesicles. The telencephalon becomes the left and right cerebral cortex; the diencephalon becomes the thalamus, hypothalamus, and pineal gland; the mesencephalon becomes the midbrain; the metencephalon becomes the pons and cerebellum; and the myelencephalon becomes the medulla oblongata. The rest of the neural tube develops into the spinal cord.
Image by Lecturio.
The choroid plexus (yellow) is developed from the ependymal lining of the lateral, 3rd, and 4th ventricles. The function of the choroid plexus is filtration of the blood to release ultrafiltrate into ventricles in the form of CSF.
Image by Lecturio.
As the neural tube grows, it develops into a series of bends in the sagittal plane. Cervical flexure occurs between the spinal cord and the rhombencephalon; cephalic flexure occurs between the prosencephalon and the mesencephalon.
Image by Lecturio.
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
- Alar plate (sensory):
- 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.
The marginal zone is the area adjacent to the mantle zone. The cells proliferate from the ventricular zone to fill up the gap so that the area for the spinal cord will be limited.
Image by Lecturio.
The basal plate becomes the anterior horn of the spinal cord, and its neurons have a motor function. The neural tube is closed by a roof plate posteriorly and a floor plate anteriorly.
Image by Lecturio.
In the cranial medulla, the roof plate is more opened out and has an “open book” appearance. Sulcus limitans still separates the alar and basal plates, but they are now located laterally (alar plate) and medially (basal plate).
Image by Lecturio.
As the cranial medulla develops, the olivary nucleus appears; it is a distinctive structure in the brain stem, as it acts as a sensory relay area.
Image by Lecturio.
Pontine nuclei are going to be sensory in origin, they migrate anterior to the basal plate.
Image by Lecturio.
The pons sits ventrally and anteriorly. The cerebellum develops as an extension of the neuroepithelium.
Image by Lecturio.
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.
The interventricular foramen connects the lateral ventricles to the 3rd ventricle.
Image by Lecturio.
Neurons travel from the ventricular zone to the marginal zone by following glial cells that extend processes throughout the entire length.
Image by Lecturio.
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
Stomodeum is surrounded by mandibular prominence (blue) inferiorly, maxillary prominences (yellow) laterally, and frontonasal prominence (green) superiorly.
Image by Lecturio.
Nasolacrimal marks the area of the junction between the frontonasal prominence (green) and the maxillary prominence (yellow).
Image by Lecturio.
After there is contact between the median nasal prominences (green) and the maxillary prominence (yellow), they stretch inferiorly and fuse with the maxillary prominences to form the cheek and upper lip.
Image by Lecturio.
Median nasal (green) and maxillary (yellow) prominences spread outward to form the upper lip. This process is followed by the fusion of right and left medial nasal prominences to form the middle of the nose and the philtrum along the midline of the upper lip.
Image by Lecturio.
Final image of the developed face. Mandibular prominence (blue) forms the mandible and the area anterior to the ear.
Image by Lecturio.
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.
References
- Sadler, T. W. (2014). Langman’ Medical Embryology.
- Lindsay M. Biga et al. Anatomy & Physiology. Retrieved 21 Oct, 2020, from https://open.oregonstate.education/aandp/
- Fishman MA. Hydrocephalus. (1978). In: Neurological Pathophysiology, Eliasson SG, Prensky AL, Hardin WB (Eds), Oxford, New York.
- Arnold WH, Meiselbach V. (2009). 3-D reconstruction of a human fetus with combined holoprosencephaly and cyclopia. Head Face Med. doi: 10.1186/1746-160X-5-14.
- Shkoukani MA, Chen M, Vong A. (2013). Cleft lip – a comprehensive review. Front Pediatrics. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873527/
