Neuronal Migration Case File

Neuronal Migration Case File

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

CASE 16

A 2-week-old baby boy is brought into the emergency room by ambulance after he started shaking uncontrollably during his sleep. When the paramedics and transport team arrived at the home, he was still shaking with his eyes deviated upward. When he stopped shaking, he remained unresponsive with his head next to a puddle of vomit. At the hospital, he was more arousable, but irritable on examination. The mother states that the infant had an uncomplicated gestation and birth history. There haven’t been any issues that concerned the parents—no family history of diseases, no recent exposures to sick persons, and no fevers. They did notice that he coughed a lot during and after his feedings. Examination of the baby was normal, until a second episode of generalized involuntary stiffness and shaking occurred. The infant was intubated and placed on a mechanical ventilator to help him breathe and stabilized with medications. An emergent head computed tomography (CT) scan was obtained, and the boy was taken to the intensive care unit. The patient was diagnosed with lissencephaly (LIS).

• How would the brain appear grossly in this patient?
• What is the etiology of this disorder?
• Where in the developing brain are neurons formed, and by what process do neurons move from their birthplace to their ultimate location?

ANSWERS TO CASE 16: NEURONAL MIGRATION

Summary: This baby boy was previously healthy before he presented acutely with generalized seizures. There was no evidence of a gross neurological deficit or any significant developmental delay. The head CT demonstrated impaired cerebral cortical structure with loss of the normal cortical involutions and gyrations, giving a “smooth” appearance to the cerebral cortex. A diagnosis of lissencephaly (LIS) was made. The only other notable abnormality was some mild muscle stiffness in his extremities.

• Appearance of brain: Smooth or nearly smooth cerebral surface lacking the normal gyral convolutions. LIS is always associated with an abnormally thick cortex, reduced or abnormal lamination, and diffuse neuronal heterotopia (displaced neurons).
• Etiology: LIS occurs because of a disruption of normal embryogenesis in the brain. Migration of postmitotic neurons from the ventricular zone (VZ, ie, area surrounding the ventricles) to the cortical plate during nervous system development is defective, resulting in brain malformations, including human LIS.
• Origins of neurons and neuronal migration: Though several neurogenic zones have been identified in the brain, most require further study. The VZ is the most prominent neurogenic zone and newly formed neuroblasts migrate radially to differentiate into glial cells, and also via the rostral migratory system to form neurons in the olfactory bulb.

CLINICAL CORRELATIONS

Classical LIS consists of various features: (1) diffuse or widespread agyriapachygyria, (2) an abnormally thick cortex, (3) enlarged ventricles without hydrocephalus, (4) frequently abnormal corpus callosum, (5) grossly normal brainstem and cerebellum, (6) normal or slightly small head circumference, and (7) slow head growth. A study of LIS in The Netherlands demonstrated a prevalence of approximately 12 cases per million births while data from the United States showed rates of 4–11 per million births. Together, these malformations constitute a continuum, the agyria-pachygyria spectrum of malformations. Not unlike other disorders, LIS can occur in varying degrees, however, the affected children will generally have mental retardation, seizure disorder, difficulty swallowing and eating, difficulty controlling his/her muscles, stiffness or spasticity of arms and legs, and slowed growth and developmental delays. The identification of the human genes responsible for LIS has advanced the knowledge of how neurons migrate. The first human neuronal migration gene to be cloned was LIS1. This gene encodes a regulatory subunit of an enzyme, termed platelet-activating factor (PAF)-acetylhydrolase. This enzyme catalyzes the release of potent phospholipids that act as signaling proteins within neurons and interacts with tubulin to suppress microtubule dynamics. The highest levels of LIS1 are detected in the developing cortex, consistent with the protein’s putative role in neuronal migration. Mutations in LIS1 disrupt the structure or cytoskeleton of neurons. This cytoskeleton is made up of proteins (like tubulin) that give cells their distinctive shapes and normal cellular movement requires regulated rearrangements of this cellular structure. Disruptions of the cytoskeleton and its flexibility affect the ability of neurons to migrate normally and are thought to lead to the disrupted cortical pattern seen in children with LIS. Another gene XLIS, which has been identified in X-linked LIS, also interacts with the protein tubulin. Thus, the cytoskeleton, through analysis of these human disorders, plays a key and critical role in the normal migration of neurons.

APPROACH TO NEURAL MIGRATION

Objectives

1. Understand the patterns of neural migration in the nervous system.
2. Explain the different types of signals that cells respond to during neural migration.
3. Appreciate the role of the internal and external molecular processes that dictate the process.

Definitions

Radial migration: A form of neural migration that occurs as nascent neurons travel from the VZ radially out toward the pial surface.

Radial glial cells: A type of glial cell that forms a physical scaffold for migration with its processes that extend from the VZ out to the pial surface.

Tangential migration: A form of neural migration, also called nonradial migration, that does not require interaction with radial glial cell processes.

Permissive factor: A signal that passively allows a process to occur, without actively promoting its occurrence, for example, an abundance of nutrients is a permissive factor in cellular growth.

Extracellular matrix (ECM): The network of glycoproteins, proteoglycans, and hyaluronic acid that defines the space in a tissue that is not part of a cell.

Cell adhesion molecules (CAMs): A family of cell membrane–associated proteins that interact and bind with extracellular molecules or ligands. They can transmit signals through the cell membrane to the intracellular cytoskeleton.

Discussion

After a newly-born neuron exits mitosis and becomes committed to the neuronal lineage, it must leave its VZ birthplace and travel to the appropriate laminar position. This neural migration can occur by three general mechanisms: two forms of radial migration (somal translocation and locomotion) and a nonradial or tangential migration.

Postmitotic neurons migrate radially away from the VZ toward the outer pial surface to reach the top of the cortical plate. There, they assemble into layers with distinct patterns of cortical connections. Radial migration can occur via two methods: somal translocation and glia-guided locomotion. Somal translocation consists of movement of the neuron’s soma (cell body) and nucleus toward the cortical plate by selectively releasing the ventricular attachment site while maintaining their pial attachment site. Glia-guided locomotion occurs by movement along the scaffold formed by the radially oriented processes of the radial glial. The early-generated neurons predominantly use somal translocation when the ventricular-pial distance is shorter. Latermigrating pyramidal neurons first use glia-guided locomotion and then subsequently switch to somal translocation as they move past earlier generated neurons. These neurons use the radial glia processes as their primary migratory guides, forming specialized membrane contacts with the cell processes.

Until recently, the predominant model of neural migration was that the vast majority of neurons utilized radial migration along glial processes. However, recent evidence has forced a revision of this model. In the developing neocortex, most excitatory glutamatergic, pyramidal neurons do follow radial migration; however, most GABAergic, nonpyramidal interneurons travel tangentially. These neurons do not appear to use the radial glial processes or other specific cellular scaffolds.

Movement of neuronal cells from their site of birth in the VZ to their specific cortical destination relies on three cellular events: initiation, maintenance, and termination. In turn, the molecular mechanisms that regulate all three cellular processes rely upon cell–cell recognition and adhesive interactions between neurons, glia, and the ECM.

The initiation of migration must occur along appropriate pathways and/or substrates. Reorganization of the actin-based cytoskeleton appears responsible for priming the neuron for migration. These instructive factors may be extracellular signals present in the VZ. Subsequent cell–cell interactions form junctional domains in the cell membrane. In the radial migration stream, the neurons interact with the processes of the radial glia through these domains. The internal microtubule-based cytoskeletal components subsequently associate with these junctional domains to provide the force required for active cellular movement. Mutations in genes responsible for this maintenance phase of migration have been linked to human diseases, like LIS. Many of these mutations occur in proteins responsible for interactions with the microtubule-based cytoskeleton. Extracellular signals from the ECM appear to modulate this motility, via interactions with the integrin family of CAMs. The many subtypes of integrins have different molecular adhesive characteristics and are associated with varied intracellular signal transduction pathways. Thus, the specific integrin expression on the neuron surface and interactions with the ligands in the ECM and other cells can modulate the pattern of migration from initiation to termination. In fact, the destination tissue itself may relate the signals to stop the migration process by changing the ligand environment— whether from afferent fibers in the target zone, the destination neuronal population, or changes in the terminal radial glia process.

COMPREHENSION QUESTIONS

Refer to the following case scenarios to answer questions 16.1-16.2:

A 14-year-old girl is brought into your office with the complaint of the recent development of periods of odd behaviors and movements. She is diagnosed with complex partial epilepsy, and a brain MRI is ordered. On MRI, a round nodule of what looks like gray matter is seen adjacent to the lateral ventricle, beneath the normal periventricular white matter.

[16.1] An error in what process in responsible for this inappropriately located gray matter?

A. Neurogenesis

B. Radial glial migration

C. Tangential neuronal migration

D. Termination of migration

[16.2] From which area in the developing brain did these improperly located neurons originate?

A. Ventricular Zone

B. Cortex

C. Volar plate

D. Dorsal plate

[16.3] A 35-year-old male patient is brought into the emergency department by friends who found him laying on the floor of his apartment, unresponsive, with an empty bottle of wine and a bottle of valium on the table near him. On examination you note that the patient is unresponsive, with shallow respirations. You recall that both benzodiazepines (the class of drugs to which valium belongs) and alcohol increase the effects of GABA in the CNS. The neurons that normally release GABA migrate by which mechanism?

A. Radial glial migration

B. Somal translocation radial migration

C. Tangential migration

D. They do not migrate

Answers

[16.1] B. The child in this scenario has subcortical heterotopia, a disease which is thought to arise from a disorder in radial glial migration of neurons, rather than a defect in tangential migration of neurons. In this condition, neurons in the brain are located inappropriately below the cortex. This is caused by a failure of the neurons to migrate from their originating location in the VZ to their proper place in the cortex. The neurons are generated correctly, so there is no error in neurogenesis, nor is there a failure to stop migrating.

[16.2] A. Neurons that ultimately reside (or are supposed to reside) in the cortex of the brain originate from neural precursor cells in the Ventricular Zone, and then migrate to their final locations. These final locations could include the cortex, or the dorsal or volar plate in the developing brainstem and spinal cord.

[16.3] C. GABAergic neurons migrate via tangential migration. Recently it has become known that there are multiple mechanisms by which neurons migrate from the VZ to their final location. It appears that excitatory neurons tend to migrate radially, via radial glial migration or nonglial guided somal translocation. Inhibitory GABAergic neurons, however, seem to migrate tangentially, and do not utilize any sort of glial mediated guidance.

NEUROSCIENCE PEARLS ❖ Specific neuronal connections and networks are a result of appropriate migration and final destination of neurons. ❖ Cell–cell recognition and adhesive interactions between various cells and the surrounding environment are critical in regulating migration. ❖ The cellular cytoskeleton through regulated reorganization makes migration possible.

REFERENCES

Couillard-Despres S, Winkler J, Uyanik U, Aigner L. Molecular mechanisms of neuronal migration disorders, quo vadis? Curr Mol Med. 2001;1:677-688. 

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

Kato M, Dobyns WB. Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet. 2003;12(Review Issue 1):R89-R96. 

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

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