Formation of The Cerebral Cortex Case File

Formation of The Cerebral Cortex Case File

EUGENE C.TOY, MD, RAHUL JANDIAL, MD, PhD, EVAN YALE SNYDER, MD, PhD, MARTIN T. PAUKERT, MD

CASE 17

A 28-year-old pregnant woman presents to her obstetrician’s office for a routine prenatal appointment. She is a healthy person without any medical conditions and has been taking her prenatal vitamins and has stopped drinking all alcoholic beverages, as instructed. She and her husband are excited about the pregnancy. The ultrasound examination at 12 weeks confirmed a single fetus with good placental attachment and cardiac function. There was some question regarding the head size, so a second ultrasound was obtained at 18 weeks. This examination was more detailed and revealed incomplete separation of the cerebral ventricles. A perinatologist who specializes in developmental malformations was consulted, and a follow-up magnetic resonance imaging (MRI) scan was obtained. This detailed imaging study confirmed the incomplete division of the embryonic forebrain into distinct lateral cerebral hemispheres. The diagnosis of holoprosencephaly (HPE) was made based upon the MRI.

• What part of the developing brain is affected in this condition?
• What is the mechanism of this developmental abnormality?

ANSWERS TO CASE 17: FORMATION OF THE CEREBRAL CORTEX

Summary: This mid-gestational fetus is diagnosed with holoprosencephaly (HPE). The remainder of the gestation and pregnancy was uneventful. A scheduled elective cesarean section delivery was performed at full-term gestational age.

• Brain structure affected: This disorder is characterized by failure of the prosencephalon, or forebrain of the embryo, to develop.
• Mechanism: The prosencephalon develops at the tip of the neural tube at around 3 weeks in human embryos, and will be further subdivided into diencephalon and telencephalon, and by the fifth or sixth week has divided bilaterally into cerebral hemisphere. HPE results when this cleavage fails to occur.

CLINICAL CORRELATIONS

HPE is a complex congenital brain malformation characterized by failure of the forebrain to bifurcate into two hemispheres, a process normally complete by the fifth week of gestation. It is the most common developmental defect of the forebrain and midface in humans, occurring in 1 in 250 pregnancies. Since only 3% of fetuses with HPE survive to delivery, the live birth prevalence is only approximately 1 in 10,000. The majority of cases, up to two thirds, consist of the most serious form, alobar HPE. The HPE phenotypes are distributed along a continuum:

1. Alobar HPE (most severe)—the brain is not divided and there are severe abnormalities: an absence of the interhemispheric fissure, a single primitive ventricle, fused thalami, and absent midline structures like the third ventricle, olfactory bulbs and tracts, and optic tracts.
2. Semilobar HPE (moderate)—the brain is partially divided and there are some moderate abnormalities: there are two hemispheres in the rear but not in the front of the brain (partially separated cerebral hemispheres and a single ventricular cavity).
3. Lobar HPE (mild)—the brain is divided and there are some mild abnormalities: there is a well-developed interhemispheric fissure but some midline structures remain fused.
4. Middle interhemispheric variant of HPE (MIHV)—the middle of the brain (posterior frontal and parietal lobes) are not distinctly separated.

Prognosis, as would be expected, varies depending on disease severity and associated malformations. Patients with alobar HPE have a survival rate of approximately 50% by 4–5 months of age and approximately 20% at 1 year of life. Isolated semilobar and lobar HPE have empiric survival rates of approximately 50% to 1 year. Almost all survivors have some degree of developmental delay presenting with mental retardation usually correlated to the severity of HPE. Feeding difficulties leading to aspiration pneumonia and/or failure to thrive frequently occur in individuals within all subtypes. The diverse etiologies that lead to HPE highlight the susceptibility of early nervous system development to perturbation, either from genetic alterations, epigenetic factors, or both. The common denominator in HPE is there is failure of cleavage of the prosencephalon which gives rise to the cerebral hemispheres and diencephalon during early first trimester (5-6 weeks), resulting in persistent fusion of the cerebral cortices. The best known genetic model for the disease is the sonic hedgehog (shh) signaling that occurs during cortical development. The mouse mutants that have disrupted shh gene expression develop the murine equivalent of HPE, complete with cyclopia. In humans, mutations in shh have been found in 17% of familial and 3.7% of sporadic cases of HPE. Shh is involved in multiple developmental events at various times during embryogenesis. Shh participates in the establishment of the left–right axis, specification of the floor plate and ventral spinal cord, as well as ventral identity of the brain along the entire rostral–caudal central nervous system. Later during embryogenesis, shh has a crucial role in the development of various structures: the limbs, the pituitary gland, the neural crest cells, the midbrain, the cerebellum, the eyes, and the face. Other genes that have been linked to the shh molecular pathway also result in HPE phenotypes when mutated—PTCH, GLI2, ZIC2, and DHCR7.

APPROACH TO FORMATION OF THE CEREBRAL CORTEX

Objectives

1. Understand the multiple events that occur in the development of the cerebral cortex.
2. Be able to relate the types of molecular cues involved.
3. Appreciate the importance of the chemospecificity hypothesis in elaborating the molecular basis of signaling interactions.

Definitions

Neurogenesis: The mechanism for generating a neuron from a population of neuroepithelial sheet of cells.

Neurulation: The developmental process by which the neural plate fuses into the neural tube. The process begins in the cervical region and progresses in both directions, first closing the cranial neuropore, followed by the caudal neuropore.

Cell fate determination: The developmental journey during which precursor cells begin with many possible fates and are progressively limited in their potential, until they finally differentiate into a mature cell.

Neural migration: The spatial translocation of a nascent premature neuron from the ventricular zone to its final destination; in the cortex, to a specific cortical layer and position.

Axon guidance: The mechanism by which a neuron sends a cellular extension or axon over sometimes great distances—bypassing billions of potential, but inappropriate targets—before terminating in the correct area.

Growth cone: The specialized terminal apparatus on the leading edge of an axonal process that can recognize (sensory function) and mechanically respond (motor function) to guidance cues.

Attractant factors: A molecular signal that induces a growth cone to grow toward the source.

Repellant factors: A molecular signal that induces a growth cone to grow away from the source.

Synaptogenesis: The process of forming a synapse, or functional connection between two neurons. It consists of the formation of an appropriate connection and the maturation of the pre- and postsynaptic terminals into mature functional units.

DISCUSSION

The central nervous system is a complex system, and the brain as the most specialized area of the CNS is more elaborate, yet. The cerebral hemispheres, the latest evolutionary advancement in the nervous system raises the level of complexity even further. The mathematics are prodigious—the human cerebral cortices contain an estimated 20 billion neurons, and each cortical neuron is connected to upward of 10,000 other neurons. These billions of cells that make trillions of connections all start from a single cell.

The cerebral cortex relies on the same basic principles of development that the rest of the nervous system utilizes. During early neurogenesis, neural progenitors must be specified in the neuroectoderm and begin to adopt a fate separate from their ectodermal brethren. These precursor cells must expand and form first a neural plate then proceed to invaginate and form the neural tube, via continued neurogenesis and neurulation. As immature neurons are born in the ventricular zone, they experience various intrinsic and extrinsic signals that begin to establish their identity. This fate determination occurs through temporal specification, spatial specification, and other determining factors. As these neurons become increasingly “educated” in their eventual fate, they are forced to migrate to their cortical destination through a complex environment consisting of extracellular matrix (ECM) and numerous cell populations, all sending out an extensive repertoire of attractant and repellant cues (neuronal migration). The use of similar cues guides the leading processes of migrating neurons to form axonal projections to their destined target (axon guidance) and establish a functional connection or synapse (synaptogenesis) with appropriate targets. It is these final steps, the labyrinth of connections and the computational networks they define, that are the distinguishing mark of the cerebral cortex.

The central nervous system begins to adopt a “cortical fate” with the early establishment of spatial patterning. The regional patterning of the forebrain relies upon the establishment of an anterior–posterior or rostral–caudal axis. This axis defines the first three initial vesicular enlargements in the neural tube (from anterior to posterior): the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain). Further development of the prosencephalon results in an additional enlargement, separating the forebrain into the telencephalon and diencephalon. It is this telencephalon that is the embryologic precursor to the cerebral cortices. The developmental divergence continues as the spatial and connectivity patterns of neurons within a functional neural circuit are so complex that they require a special set of mechanisms.

Axon guidance involves the targeting of a specific neuron’s axon to the appropriate target. Early developmental evidence resulted in the chemospecificity hypothesis, first proposed by Roger Sperry in 1963, which stated that chemical matching between axons and their target tissues was responsible for appropriate guidance. This model suggested the existence of “recognition molecules” that were responsible for the matching. The chemospecificity hypothesis posits that signaling molecules at targets provide positional information in the form of gradients that would be detected by complementary gradients of receptors on axons to guide their growth. For this seminal idea in neurobiology, Roger Sperry was awarded the Nobel Prize. The leading process of the axon, the growth cone, is responsible for sensing these recognition cues and responding to them. Axonal growth cone movement toward its final destination occurs through polymerization or depolymerization of actin in the fingerlike projections of the growth cone. Molecules bind to receptors on the growth cone and cause a signaling cascade that results in polymerization.

Today, a vast array of molecules has been discovered that exert either attractant or repellent forces on the growing axons. In addition, many of these molecules can be attached to other cells or the extracellular environment and act over short distances, or they can be secreted, diffusible molecules that act over longer distances. These short-range interactions can be attractive: the laminins in the ECM partner with specific integrin proteins in the membrane of growth cones or the cadherin family or immunoglobulin superfamily of cell surface proteins can mediate cell–cell compatibility. They can also be repulsive; the gradient of ephrin protein ligand expressed in the target inhibits growth cones expressing the corresponding eph kinases. In addition, the soluble proteins like netrin 1 that act at long distances can have both attractive (if the growth cone expresses the DCC receptor) or repulsive (if it expresses receptors like unc-40) effects on axonal guidance.

Once axonal guidance leads to the appropriate target tissue, the process of forming a functional connection or synapse can occur. This formation of synapses, or synaptogenesis, is the key to the final step of cortical and nervous system development, because it allows the information-processing circuit to function. Once neurons are situated, synapse formation occurs when pre- and postsynapse contact each other by molecular interaction between the two cells. Neurologin then allows for the clustering of vesicles within the presynaptic terminal (see Figure 17-1).

Figure 17-1. Cytoarchitectural zones of the human cerebral cortex according to Brodmann. A. Lateral surface, B. Medial surface, C. Basal inferior surface. (With permission from Adam and Victor’s Principles of Neurology. 7th ed. Figure 22-2. page 465.)

COMPREHENSION QUESTIONS

[17.1] An 82-year-old man is being evaluated for memory loss and cognitive difficulties. An MRI shows that he has diffuse cortical atrophy with compensatory enlargement of his ventricles, consistent with Alzheimer disease. From which embryologic precursor does the cerebral cortex arise?

A. Diencephalon

B. Mesencephalon

C. Telencephalon

D. Rhombencephalon

[17.2] What type of interactions are used to guide the growth of axons so that they reach their appropriate destination?

A. Short-range contact inhibition only

B. Diffusion gradient inhibition and contact attraction only

C. Contact inhibition and diffusion gradient attraction only

D. Contact inhibition and attraction as well as diffusion gradient attraction and inhibition

[17.3] Which of the following places the developmental events in the correct chronological order?

A. Neurogenesis → Neural migration → Synaptogenesis → Axonal pathfinding

B. Neurogenesis → Neural migration → Axonal pathfinding → Synaptogenesis

C. Neural migration → Neurogenesis → Synaptogenesis → Axonal pathfinding

D. Neurogenesis → Axonal pathfinding → Neural migration → Synaptogenesis

Answers

[17.1] C. The telencephalon, which arises from the prosencephalon, is the rostral-most swelling of the neural tube, and ultimately develops into the cerebral cortex. The diencephalon becomes the thalamus, epithalamus, subthalamus, and hypothalamus, the mesencephalon becomes the midbrain, and rhombencephalon becomes the pons, medulla, and cerebellum.

[17.2] D. In the process of axonal pathfinding, there are many different cues that guide the axon to its ultimate destination such as attractive/ repulsive contact cues and attractive/repulsive diffusion gradient cues. Since the axonal growth cone of each different type of neuron expresses different receptor molecules, they all respond to the cues differently, allowing them all to reach their own appropriate target.

[17.3] B. The correct order is that first the neurons are formed from precursor cells in the ventricular zone, then they migrate via one of several methods to their final location in the cortex. Following migration, the neurons send out axonal growth cones that respond to attractive and repulsive signals to reach the appropriate target, where they can undergo synaptogenesis to mature the connection between presynaptic and postsynaptic cell.

NEUROSCIENCE PEARLS ❖ The cerebral cortices develop through a series of conserved and overlapping mechanisms shared with other parts of the nervous system. ❖ Axonal guidance is reliant on a balance of attractant and repellant factors. ❖ Specific molecules mediate chemical interactions between the growing axon and target tissues.

REFERENCES

Cohen MM, Jr. Holoprosencephaly: clinical, anatomic, and molecular dimensions. Birth Defects Res. 2006;76(pt A):658-673. 

Hahn JS, Plawner LL. Evaluation and management of children with holoprosencephaly. Pediatr Neurol. 2004;31:79-88. 

Kandel E, Schwartz J, Jessell T, eds. Principles of Neural Science. 4th ed. New York: McGraw-Hill; 1991. 

Rao MS, Jacobson M, eds. Developmental Neurobiology. 4th ed. New York: Kluwer Academic/Plenum Publishers; 2005. 

Roessler E, Muenke M. How a hedgehog might see holoprosencephaly. Hum Mol Genet. 2003;12(Review Issue 1):R15-R25. 

Sadler TW, ed. Langman’s Medical Embryology. 7th ed. Baltimore, MD: Williams and Wilkins; 1995.

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