This article will help you understand how the brain develops in a human embryo from the very beginning: gastrulation, the formation and fate of the primitive streak, neurulation with possible neurocristopathies, closure of the neuropores, embryonic folding, regionalization of the brain, and potential birth defects of the brain. After that, the article will focus on the development of the cranium and possible cranial birth defects.

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fetal cranium

Image: “Skull of a new-born child from the side.” by Dr. Johannes Sobotta – Sobotta’s Atlas and Text-book of Human Anatomy 1909. License: Public Domain


Gastrulation

The entire nervous system is derived from the neuroectoderm which is a part of ectoderm – one of the three basic germ layers. These germ layers are known as ectoderm, mesoderm and endoderm.

Gastrulation is the name of the embryological process that results in the formation of the three germ layers. All embryonic tissues are derived from these germ layers hence gastrulation marks the beginning of morphogenesis, i.e development of the body. This takes place in the third week of the human development. This is also usual when the first symptoms of pregnancy start arising. Gastrula is the term used to describe the trilaminar structure.

Various signalling molecules are involved in the process of gastrulation and the formation of tissues from the three germ layers. These molecules include FGF (Fibroblast Growth Factor), Sonic hedgehog, Tgifs (TG-interacting factors) and bone morphogenetic proteins.

Formation and Fate of the Primitive Streak

primitive streak gray17

Image: “The primitive streak.” by Henry Vandyke Carter, Henry Gray (1918) Anatomy of the Human Body. Bartleby.com: Gray’s Anatomy, Plate 17 . License: Public Domain

Primitive streak is the first sign of occurrence of gastrulation on the blastula (the previous bilaminar structure). The function of the primitive streak is to establish bilateral symmetry in a human body and giving the embryo a craniocaudal axis, hence helping to identify its cranial and caudal ends, dorsal and ventral surfaces as well as the left and right sides.

The primitive streak occurs caudally, on the median plane of the dorsal surface of the embryonic disc. It keeps getting longer as more and more cells are added to its caudal surface. At its cranial surface, cells proliferate to produce a primitive node.

Primitive groove is an invagination of the primitive streak continuous with the invagination in the primitive node, called the primitive pit.

Cells from the deeper surface of the primitive streak leave to form mesoderm, which gives rise to various supportive tissues of the embryo discussed later. Cells from the primitive node, epiblast and other areas of the primitive streak give rise to the endoderm. Cells that remain in the epiblast (the most external layer of the blastula) form the ectoderm.

Once the primitive streak has given rise to mesoderm and the remaining germ layers, it regresses by the end of the fourth week as an insignificant structure in the embryo’s sacrococcygeal region.

Sacrococcygeal teratoma is the result of persisting remnants of the primitive streak.

Neurulation

Neurulation is the process that involves the formation of the neural tube through the development of the neural plate and the closing of the neural folds.

neurulation

Image: “Neural crest formation during neurulation.” by NikNaks – File:Neural_Crest.png. License: Public Domain

Neurulation begins in the fourth week. Location of neurulation is initially between the 4th to 6th somite (bilateral blocks of paraxial mesoderm).

The following molecules play vital roles in neurulation:

  • Noggin – an inductor protein
  • BMP-4 – bone morphogenetic protein
  • N-CAM – a neural cell adhesion molecule
  • FGF-8 – Fibroblast Growth Factor

Notochord is the structure that is responsible for inducing the formation of the neuroectoderm (which gives rise to the nervous system). Notochord is a median cellular cord that is developed by the migration of mesenchymal cells from the cranial aspect of the primitive node and pit. Notochord, once acquiring a lumen, transforms into the notochordal canal. Notochord also makes the nucleus pulposus of the intervertebral disc in an adult.

The notochord induces the formation of the neural plate by causing the thickening and elongation of the embryonic ectoderm laying over it. The neural plate, in turn, gives rise to the neuroectoderm that is responsible for the formation of the central nervous system (rest of neuroectoderm derivatives are discussed later).

On the 18th day, an invagination takes place in the middle of the neural plate and forms the neural groove with neural folds on either side.

Neural folds start approximating to fuse on the median plane; once fused together, they convert the neural plate into the neural tube. Fusion of the neural folds happens at the level of the 5th somite and continues both cranially and caudally.

It is the neural tube that further differentiates into primary brain vesicles that convert into different regions of the human brain. The neural canal, lumen of the neural tube, communicates openly with the amniotic fluid in the cavity and gives rise to the ventricular system of the brain and spinal cord.

Neural crest cells are neuroectodermal cells found along the lateral border of the neural plate, on the internal margin of the neural folds. During the fusion of the neural folds, these cells disassociate themselves from the inner margins of the neural folds, lose their epithelial nature and form the neural crest, which is located between the neural tube and the overlying ectoderm layer. This process is mediated by BMP-4 and BMP-7.

Wnt/β-catenin is the signalling molecule responsible for activating the Gbx2 gene that is vital for the formation of the neural crest.

Neural crest cells migrate to different regions of the embryo and give rise to various structures (neural crest cells derivations are discussed later). The migration of neural crest cells to the somites via redefined pathways is made possible by molecular interaction of particular signalling molecules, transcription factors and genes like FoxD3, Sox9 and Sox10.

Neurocristopathy is the term used to define the disorders that occur due to maldevelopment of the neural crest cells.

molecular interaction of various genes, transcription factors and signaling molecules to allow migration of neural crest cells to different regions

Image: “Molecular interaction of various genes, transcription factors and signalling molecules to allow migration of neural crest cells to different regions.” License: Public Domain

Examples of diseases with neural crest cells origin include medullary carcinoma of the thyroid, Hirschsprung disease, Digeorge syndrome, Schwannoma and neurofibromatosis type 1.

Closure of the Neuropores

Closure of the neuropores holds clinical significance as the failure to do so can lead to various congenital neural tube defects.

anencephaly

Image: “A side view of the anencephalic fetus.” by Ed Uthman, MD – http://www.geocities.com/HotSprings/Falls/7780/images/anencephaly.html. License: Public Domain

  1. First part of the neural tube to close is the middle part – it occurs at 22nd day.
  2. Second part to close is the rostral part, i.e the rostral neuropore – it occurs on the 25th day.
  3. Last part to close is the caudal neuropore – its closure occurs on the 27th day.

In all neural tube defects, there will be a rise of alpha-fetoprotein and acetylcholinesterase in the amniotic fluid. These two markers help identify neural tube defects in the fetus. Examples of neural tube defects include anencephaly and spina bifida.

Anencephaly: upper neurotube defect that occurs due to the failure of the anterior (rostral) neuropore to close during the 4th week of development. The brain and bony cranial vault that encases it fail to develop. It is incompatible with life. This disorder is easily diagnosed by ultrasound.

An illustration of an infant with spina bifida

Image: “An illustration of an infant with spina bifida.” by Centers for Disease Control and Prevention – Centers for Disease Control and Prevention. License: Public Domain

Spina bifida: failure of the caudal neuropore to close and induce bone development around it. There are four types, the mildest form being spinal bifida occulta (that is asymptomatic except a tuft of hair over the defect) and the severest form being spina bifida with myeloschisis (spinal cord can be seen outside of the vertebral column – incompatible with life).

Embryonic Folding

Growth of the neural tube causes two types of embryonic folding: longitudinal and transverse (flexion). This converts the flat trilaminar structure into a cylindrical-shaped embryo.

These foldings occur at the same time.

  • Longitudinal folding:
  1. Headfold – neural folds project dorsally into the amniotic cavity whereas the forebrain grows and projects cranially, hanging over the primitive heart.
  2. Tailfold – folding of the caudal end. This results from the caudal and dorsal growth of the neural tube. The primitive streak moves from cranial to caudal position after folding takes place.
  • Transverse folding/flexion – results in the embryo detaching from its embryonic membranes, attached only by the umbilical cord. It produces the right and left lateral folds as the two lateral parts of the body roll inwards towards the midline.

Regionalization of the Brain

Neural tube initially gives rise to three primary vesicles, which further divide into five primary vesicles that give us the fully formed brain and spinal cord.

The three primary vesicles and two flexures develop in the 4th week.

  • Three vesicles:

    4 week human embryo brain

    Image: “Brain of a four-week old human embryo.” by Kurzon – Own work. License: Public Domain

  1. Prosencephalon – forebrain
  2. Mesencephalon – midbrain
  3. Rhombencephalon – hindbrain
  • Five primary vesicles derived from the three primary vesicles:
  1. Prosencephalon: telencephalon and diencephalon
  2. Mesecephalon remains as it is
  3. Rhombencephalon: metencephalon and myelencephalon
  • Adult brain structures derived from the five primary vesicles:

    nervous system of a 6 week human embryo

    Image: “A diagram showing the brain and major nerves of a 6 week old human embryo. 1. olfactory 2. optic 3. oculomotor 4. trochlear 5. trigeminal sensory 6. trigeminal motor 7. abducens 8. facial 9. vestibulocochlear 10. glossopharyngeal 11. vagus 12. cranial accessory 13. spinal accessory 14. hypoglossal 15. cervical I, II, III and IV” by Kurzon – Own work. License: Public Domain

  1. Telencephalon – cerebral hemisphere, caudate, putamen, amygdaloid, hippocampus, claustrum, olfactory bulbs, and lateral ventricles
  2. Diencephalon – thalamus, hypothalamus, subthalamus, epithalamus (also known as pineal gland), retina, optic, mammillary bodies, neurohypophysis, optic chiasm, optic tract nerve as well as the third ventricle
  3. Mesencephalon – midbrain and the cerebral aqueduct
  4. Metencephalon – pons, cerebellum and the fourth ventricle
  5. Myelencephalon – medulla, spinal cord and the central canal

Note: all ventricles are derived from the neural canal remnant.

cephalic flexure

Image: “The cephalic flexure.” by Henry Vandyke Carter, Henry Gray (1918) Anatomy of the Human Body. Bartleby.com: Gray’s Anatomy, Plate 651. License: Public Domain

Cephalic flexure, also called the midbrain flexure, occurs between the prosencephalon and rhombencephalon, whereas the cervical flexure is located between the prosencephalon and the future spinal cord. Pontine flexure is the junction between the metencephalon and myelencephalon.

Cephalic flexure assists in the bending of the forebrain over the anterior part of the notochord and foregut. This way, the floor of the forebrain comes on the same level as that of the hindbrain. Due to the cephalic flexure, the midbrain temporarily holds the most dorsal and prominent position in the embryo.

Birth Defects of the Brain

Microcephaly

microcephaly comparison

Image: “Side-view illustration of a baby with microcephaly (left) compared to a baby with a typical head size.” by Centers for Disease Control and Prevention. License: Public Domain

This is a developmental disorder in which the brain and calvaria are small in size with a normal size face. It presents at birth or a few months later. The infant shows severe neurological deficits like seizures, decreased cognitive, speech and motor functions. Dwarfism may also be present.

Primary microcephaly being autosomal recessive is genetic in origin. However, various external etiologies have been linked to occurrence of microcephaly. These include exposure to radiation, infections by viruses such as rubella, cytomegalovirus and recently, Zika virus. Maternal alcohol abuse during pregnancy is also a known cause.

Encephalocele

encephalocele

Image: “Illustration of a baby with encephalocele.” by Centers for Disease Control and Prevention – Centers for Disease Control and Prevention. License: CC0

Also known as cranium bifidum, this condition is a neural tube defect in which the brain and its membranes herniate out through defects in the cranium. This most commonly occurs in the occipital region. It occurs once in every 2,000 births. There are three types of encephalocele:

  1. Menigocele: the herniation only contains the meninges. The sac is filled with CSF (cerebrospinal fluid).
  2. Meningoencephalocele: the herniation includes the meninges as well as a part of the brain. The herniation is filled with CSF. Diagnosed with MRI.
  3. Meningohydroencephalocele: herniation includes the meninges, a part of the brain as well as the part of the ventricular system.

Germ Layers and Their Derivatives

Ectoderm is the most distal/outer layer of the gastrula.

The ectoderm can be divided into two categories:

  1. Surface ectoderm, which gives rise to the epidermis (skin), nails, hair, lens of eye, enamel of teeth, inner and external structures of the ear and the anterior pituitary (which is derived from the Rathke’s pouch).
  2. Neuroectoderm, which is further divided into the neural tube and neural crest cell, gives rise to the entire central and peripheral nervous system.
    1. The structures derived from the neural tube are as follows:
      • Central nervous system (brain and spinal cord)
      • Neurohypophysis (posterior pituitary)
      • Oligodendrocytes (myelinating cells of the CNS)
      • Pineal gland
      • Retina and optic nerve (although optic nerve is considered to be a cranial nerve, it is, in fact, an extension of the diencephalon; therefore, its involvement is seen as optic neuritis in multiple sclerosis, a demyelinating disease of the CNS)
      • Astrocytes.
    2. The structures derived from the neural crest cells are as follows:
      • Adrenal medulla
      • Sensory and autonomic (postganglionic) ganglia
      • Pharyngeal arch cartilage
      • Melanocytes (pigment cells) – neural crest cells migrate to the stratum basalis of the epidermis of the skin.
      • Schwann cell (myelinating cells of the PNS)
      • Meninges – arachnoid and pia mater, whereas the dura mater is derived from the mesoderm.

Neural crest cells also play an important role in the development of the aorticopulmonary septum – a defect which can give rise to congenital heart diseases like Tetrology of Fallot. Failure of their migration to the first pharyngeal arch can also lead to first arch syndromes with craniofacial abnormalities like Treacher Collins syndrome and Pierre Robin syndrome.

Mesoderm gives rise to muscles, bones, cartilage, blood vessels, all serous membranes of the body and connective tissues layers of the peripheral nerves known as the endoneurium, perineurium and epineurium.

Endoderm is responsible for giving rise to the epithelial linings of the body as well as the parenchyma of various viscera like the liver, pancreas, thyroid and salivary glands.

Development of the Cranium

Neurocranium – bones that encase the brain.

Viscerocranium – bones that make up the facial features. They are derived from the pharyngeal arches.

The skull develops from the mesenchyme that surrounds the brain. Desmocranium mesenchyme is the primordium of the cranium and the ossification centers within the desmocranium initiate the formation of the cranium.

Very important molecules that regulate osteoblast differentiation that leads to the formation of the cranium are the transforming growth factors beta (TGF- β).

The neurocranium can be divided into cartilaginous neurocranium and membranous neurocranium.

Cartilaginous neurocranium

Fusion of numerous cartilages gives a cartilaginous base, which, after ossification, forms the base of the bones of the cranium. For example, base of the occipital bone is derived from the parachordal cartilage, which forms around the cranial end of the notochord and fuses with the surrounding cartilages to give the base of occipital bone. It later expands and forms the boundaries of the foramen magnum.

Similarly, hypophysial cartilage forms alongside the developing pituitary and later gives rise to the body of the sphenoid bone. Trabeculae cranii give rise to the body of the ethmoidal bone whereas ala orbit fuse together to form the lesser wing of the sphenoid.

Membranous neurocranium

This forms the calvaria, also known as the skull cap. It occurs on the top and sides of the head. Sutures of the calvaria are dense connective tissue membranes that are found between the bones of the calvaria. Fontanelles are where sutures meet. Fontanelles, along with the soft bones of the calvaria, allow molding of the fetal cranium during birth.

Skull deformities associated with single suture synostosis

Image: “Skull deformities associated with single suture synostosis.” by Xxjamesxx – Own work. License: CC BY-SA 3.0

The flexibility of the sutures allow the brain to grow and develop after birth. The most rapid postnatal growth of the brain occurs in the first two years. The growth of the calvaria carries on until the age of 16, followed by 3-4 years of thickening of the bones.

Cranial Birth Defects

Premature closing of sutures can give rise to the following cranial defects:

  • Scaphocephaly: early closure of the sagittal suture
  • Brachycephaly: early closure of coronal suture
  • Plagiocephaly: coronal suture closes early on one side
  • Trigonocephaly: premature closure of frontal suture.
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