Development of the Nervous System [7]

Question 1

Understand the primary axes of the central nervous system, and the designations dorsal, ventral, rostral, and caudal

Answer 1

• Rostro-caudal: nose to tail
• Dorso-ventral: back to front (across rostro-caudal plane). The initially straight neural tube takes a roughly 80 degree turn during its development between the brain and brainstem→cephalic flexure.
• Sagittal: slices from side to side.
• Coronal: slices from front to back
• Axial: parallel to the ground.

Question 2

Understand the way in which the nervous system is segmented into rostrocaudal segments of telencephalon, diencephalons, mesencephalon, metencephalon, myelencephalon, and spinal cord

Answer 2

• Development of the neural tube occurs along the rostro-caudal axis as well as the dorso-ventral axis→different dorso-ventral pattern at each rostro-caudal segment.
• Development of the neural tube along its rostrocaudal axis gives rise to enlargements at the rostral end, the primary cerebral vesicles. These three primary vesicles will go on to develop into secondary cerebral vesicles:

1. Prosencephalon (telencephalic vesicles and diencephalic vesicles)
2. Mesencephalon
3. Rhombencephalon (metencephalon and myelencephalon)

Caudal to these vesicles, the neural tube and its lumen will give rise to the spinal and central canal.

Question 3

Understand the components of the ventricular system and how these relate to the rostrocaudal segments of the neural tube.

Answer 3

•Lateral ventricles→from telencephalic vesicles of the prosencphalon
Foramen of munroe (interventricular foramen)

•Third ventricle→from diencephalic vesicle
Cerebral aqueduct

•Fourth ventricle (metencephalon and myelencaphalon)
Foramen of Magendie and foramen of Lushka.

Question 4

Understand the significance of the rhombomeres, in terms of the segmental development of the hindbrain and its relationship to specific cranial nerves.

Answer 4

•Rhombomeres: These seven segments of the rhombencephalon develop because of the expression of unique combinations of Hox genes in each region. Between rombomeres, cells will differ in terms of morphology, axonal trajectories, neurotransmitter synthesis, neurotransmitter selectivity, firing properties, and synapse specificity.

The motor neurons of cranial nerves IV, V, VI, VII, IX, X, XI and XII (4,5,6,7,9,10,11 and 12) each arise from the rhombencephalon.

Each motor nerve originate from a single rhombomere or a pair of neighboring rhombomeres.

Question 5

Understand the general scheme of dorsoventral patterning of the neural tube into alar and basal plates

Answer 5

The neural progenitors in the cord develop into distinct populations based on their position along the dorsal-ventral (DV) axis.

• Closer to ventral aspect of neural tube→motor neurons→efferent
• Closer to dorsal aspect of neural tube→sensory neurons→afferent

The neural tube develops a crease, the sulcus limitans, that separate the ventral population from the dorsal population.

• Ventral population→ basal plate
• Dorsal population→alar plate

Question 6

Understand the basic scheme of dorsoventral patterning of the prosencephalon, and how this relates to the adult three-dimensional structure.

Answer 6

• The most rostral portion of the neural tube is also influenced by a morphogen gradient→Shh (produced ventrally)→dorsoventral gradient
• Before the telencephalic vesicles begin to form, the rostral neural tube develops regionally restricted DV markers, that will presage the morphological appearance of three discrete proliferative zones.

1) Dorsal: cortex
2) Lateral: lateral ganglionic eminence→putamen and globus pallidus
3) Medial: medial ganglionic eminence→caudate nucleus.

Question 7

Know when and where neurogenesis occurs

Answer 7

Primary Neurogenesis: Occurs in the ventricular zones, the layers closest to the ventricles in the brain and in the central canal in the spinal cord; Before birth

Secondary Neurogenesis: Occurs post-natally in the External Granule Layer (cerebellum), Subventricular Zone (olfactory bulb) and the Dentate Gyrus (hippocampus)

Question 8

Describe the changes in nuclear position that occur during the cell cycle of neuronal precursors.

Answer 8

During the cell cycle, the cell nucleus of proliferating neurons moves between the ventricle side of the ventricular zone to the pia side, and back again. Mitosis, and thus cell division, occurs on the ventricular surface, while DNA synthesis occurs on the pia surface.

Question 9

Describe methods used to study neurogenesis.

Answer 9

The best way to study neurogenesis is through labeling diving cells with detectable DNA precursors. The most common labels include 3H-Thymidine and bromodeoxyuridine (aka BrdU – red nuclear stain in above figure). A cell will take up the label during S phase and the progeny are tracked by the label. You can see this in real time or with fixation and staining. It can also be used with in vivo models, such as in mice.

Question 10

Know what is meant by a neuron’s birthdate. Does a neuron’s birthdate influence its differentiation?

Answer 10

A cell’s birthdate: the time it undergoes its last round of DNA synthesis (S phase). After its birthdate, a cell divides and makes the decision to exit the cell cycle from M phase.

Only post-mitotic cells differentiate. So yes, a neuron’s birthdate influences its differentiation in that it cannot differentiate until it is “born” (aka leaves the cell cycle).

Question 11

Know which brain regions are areas of secondary neurogenesis

Answer 11

x

Question 12

Describe what is known about neurogenesis in the adult brain.

Answer 12

Neurogenesis does occur in the adult brain, mostly in the dentate gyrus and subventricular zone to give rise to new neurons in the hippocampus and olfactory bulb, respectively. However, there is also cell death occurring in the adult brain, such that there is little to no increase in the number of neurons in those areas. Interestingly, neurons born post-natally appear to be more prone to cell death

Question 13

Draw and describe an asymmetric cell division.

Answer 13

When a progenitor cell in the ventricular zone divides, the plane of cleavage can be either perpendicular to the ventricular surface or parallel to the ventricular surface.

Parallel = asymmetric division

• Unequal distribution of cytoplasmic proteins, mRNAs, etcc
• One daughter cell stays attached to the ventricular surface – stays in the cell cycle
• One daughter cell is no longer attached to the ventricular surface – is now a post-mitotic neuron and will go on to migrate and differentiate

Question 14

Know factors/mechanisms that determine when a cell stops dividing and begins differentiating.

Answer 14

There are factors (prospero, numb, etc) that, in sufficiently large quantities, seem to induce the cell to stop dividing and start differentiating. When the plane of cell division is right for symmetrical division, these factors divide evenly and do not reach the threshold for differentiation. However, when the plane of division is right for asymmetrical division, these factors tend to cluster on the external side (facing the pia) such that the daughter cell that forms without contact to the ventricular wall surface has sufficient factor levels to exit the cell cycle and differentiate.

Question 15

For the cerebral cortex, know where the first-born cells are found with respect to the ventricular zone. What about the retina?

Answer 15

The cerebral cortex arises from the cortical plate, which is separated from the ventricular zone by the intermediate zone and subplate. The cells of the cerebral cortex migrate in an inside-out pattern. Cells migrate from the ventricular surface to the cortical plate. First-born cells are found at the edge of the cortical plate, closest to the ventricular surface and later born cells migrate passed these first-born cells further from the ventricular surface. This inside-out patterning of migration is unique to the cerebral cortex.

In the retina, this pattern is reversed. Ganglion cells are born first and are found furthest form the ventricular zone, while photoreceptors form last and are found closest to the ventricular zone. Thus, the retinal development follows an outside-in pattern.

Question 16

Define preplate and subplate with respect to neuronal migration.

Answer 16

After leaving the mitotic cycle, cells leave the surface of the ventricles and migrate to a new position, which leads to the formation of the preplate. As cells continue to migrate to the preplate, the preplate further divides to form four zones

1. Subplate: transient neuronal cell population that play “pioneering roles” in circuit formation
2. Intermediate zone: containing neuronal and glial cell processes
3. Cortical plate: neurons of cerebral cortex
4. Marginal zone: superficial zone adjacent to pia containing the Cajal-Retzius cells that express reelin

Question 17

Describe the role that radial glia play in neuronal migration.

Answer 17

Radial glia are specialized glia cells that extend from the ventricle to the pial surface of the developing neural tube. The radial glia are used as a guide or scaffolding for cells as they migrate from the ventricular zone to the developing cerebral cortex.

Question 18

What are the 3 stages of neuronal migration in the cerebral cortex?

Answer 18

1. Onset: cells get on the radial glia
2. Continuation: cells stay on radial glia until they have migrated to the right location
3. Stopping: cells get off the radial glia scaffolding when they reach the right location

Question 19

Know genes that play a role in neuronal migration in the cerebral cortex? Which stages of migration do they affect?

Answer 19

Onset: FLNA-actin binding

Continuation:

• LISI-protein for regulation of microtubule function
• DCX- protein for regulation of microtubule function

Stopping:

• Reeler- large extracellular protein
• Vldr and Apoer2- receptors for reelin on migrating cells in cerebellum and cerebral cortex respectively
• Dab1- intracellular protein involved in transducing reeling signal

Question 20

Know what neural crest cells are.

Answer 20

Neural crest cells arise along the edges of the neural folds between the neurectoderm and the overlying epidermis. The neural crest cells are made up of ectoderm. The fate of the neural crest cells is determined by the position on the rostro-caudal axis.

Question 21

Contrast migration of neural crest cells to radial migration in the cerebral cortex.

Answer 21

Neural crest cells migrate very quickly and without guides. Radial migration, on the other hand, is slower and requires guide cells called radial glia

Question 22

Compare and contrast “apoptosis” with “necrosis”.

Answer 22

Necrosis: death of cells due to injury or damage of cells that causes a loss of membrane integrity. Mitochondria and endoplasmic reticulum swell. Intracellular contents are released and can expose neighboring cells to toxic substances. Associated with external injury, trauma or extreme physiological changes

Apoptosis: programmed cell death that is an active process requiring the cell to make new mRNA and proteins associated with apoptotic pathways. Condensation of the cytoplasm and DNA fragmentation. Recruits phagocytes to remove the cell and prevents neighboring cells from being exposed to the intracellular contents of cells. Most common in the developing nervous system

Question 23

Know when cell death occurs in the nervous system

Answer 23

Cell death often occurs during the establishment of connection by a particular neuron population. A limited amount of neurotrophic survival factors are available and neurons compete for them at target sites, resulting in cell death

Question 24

Define and describe what are neurotrophins. What roles do they play in neuronal development?

Answer 24

Neurotrophins are a class of neurotrophic factors that are survival factors at the synapse between target and developing neuron. Neurons compete for a limited amount of these trophic factors. Activation of the receptor by neurotrophin binding causes dimerization of the Trk proteins, and recruitment of signaling molecules within the cell. The activation of this cascade results in suppression of apoptosis.

Question 25

Know the three factors that influence the ability of axons to regenerate

Answer 25

1.The ability of axons to grow.
CNS and PNS nerve axons are both able to grow inherently. PNS injuries can regenerate, CNS injuries often do not, but not as a result of the inability of the axon to grow.

2.The presence of molecules that promote growth.
Schwann cells produce NGF and other trophic factors which assist in axon regeneration. Also, fibroblast growth factor (FGF) and neurotrophins in the PNS help with this process. In contrast, the glial environment of the CNS may not express these factors well.

3.The presence of molecules and receptors that inhibit growth.CNS myelin expresses a molecule called Nogo, an inhibitory molecule which prevents axon regeneration.

Question 26

Define synapse elimination. When and where does it occur?

Answer 26

Synapse elimination is the selective removal of immature synapses formed because a neuron initially has more than one target. This is a refinement of synapses, not a net loss of synapses as the total number of synapses continues to increase.

Happens in the CNS and PNS when asynchronous or misaligned synapse firing promotes elimination.

Question 27

Describe normal postnatal changes in brain morphology

Answer 27

At birth, the density of neural connections is very low compared to the end of childhood. During the first year of life, the soma increases significantly in size and the number of dendrites increases while their spines thicken. There is a dramatic increase in the number of interconnections between neurons, and even this huge increase in the first year represents only 50% of what the number of connections will be at the end of childhood.

Question 28

How do ASD and Down’s syndrome affect normal developmental changes in neuronal morphology?

Answer 28

In kids with Autism Spectrum Disorder (ASD), the brain is normal or small at birth, but during the first few years of life the it increases in size abnormally, especially in white matter areas. Neuron bodies (soma) are small and the dendrites branch less than normal. This may be due to abnormal synapse maturation or pruning.

In kids with Down’s Syndrome, the spines of the dendrites are abnormally thin and short

Question 29

Know when myelination occurs.

Answer 29

Myelination begins in the periphery in the embryo. The CNS begins to become myelinated at the end of the first trimester in the spinal cord. Myelination reaches the brain around by the third trimester. However, myelination of cortical tracts involved in higher brain function occur post-natally while myelination of the corticospinal tract begins pre-natally but does not extend past the medulla in the caudal direction until after birth.

Question 30

Describe two ways in which function of GABA receptors is developmentally regulated.

Answer 30

GABA receptors are oligomers, meaning they have more than one subunit, and each of these subunits has multiple isoforms. Different isoforms predominate during embryonic stages than in adult stages.

GABA receptor is a chloride channel…..
Adult: equilibrium potential for chloride is near to or negative compared to the resting membrane potential, making GABA inhibitory

Embryonic: intracellular chloride is higher and thus ECl is more depolarized. Thus, GABA receptors are excitatory in the developing nervous system

Question 31

What are the segmentations of Prosencephalon?

Answer 31

Telencephalic vesicles→cerebral hemispheres (with lateral ventricles)

Diencephalic vesicles→thalamus, hypothalamus, subthalamus and epithalamus (3rd ventricle)

Question 32

What are the segmentations of Rhombencephalon?

Answer 32

Metencephalon→pons and cerebellum (4th ventricle)

Myelencephalon→medulla (4th ventricle)

Question 33

What are the segmentations of Mesencephalon?

Answer 33

Mesencephalon (does not segment any further)→midbrain

Question 34

How is the general scheme of dorsoventral patterning of the the neural tube modified at the level of the midbrain, pons, medulla and spinal cord?

Answer 34

The midbrain, pons and medulla, like the spinal cord, demonstrate variations on the alar/basal plate scheme. In their adult form, the brainstem segments are described in terms of a tectum (roof) on their most dorsal portion, a tegmentum (floor) just ventral to the ventricular lumen, and their ventrally appended structures:

• Midbrain→basis pedunculus (cerebral penduncles)
• Pons→basis pontis
• Medulla→basis pyramidalis (pyramids).

Cells in the dorsal part of the metencephalon proliferate to form the rhombic lip, which will develop into the cerebellum.

Question 35

Understand the components of the ventricular system and how these relate to the rostrocaudal segments of the neural tube.

Answer 35

The cerebral vesicles are segments of the hollow neural tube. While the vesicles develop into the adult structures of the CNS, the lumen of the neural tube also gives rise to adult CNS architecture.
Paired telencephalic vesicles lumens&raquo_space; lateral ventricles of the cerebrum.
Lumen of the diencephalon&raquo_space; the third ventricle
Mesencephalon’s lumen&raquo_space; aqueduct of Sylvius.
Lumen of the rhombencephalon (both the metencephalone and myelencephalon)&raquo_space; fourth ventricle.
Lumen of the developing spinal cord will give&raquo_space; central canal.

Question 36

Describe the stage of Onset of Neuronal Migration in the cerebral cortex

Answer 36

Cells need to get on the radial glia to begin migrating. Onset involves perturbations to the actin cytoskeleton of the migrating cell. The filamin A gene (FLNA) codes for an actin-binding crosslinking protein. Mutations in the gene lead to periventricular heterotopia (PH), a condition in which cells cannot leave the ventricular zone.

Question 37

Describe the stage of Continuation of Neuronal Migration in the cerebral cortex

Answer 37

Cells need to stay on the radial glia until they have migrated to the right location. The ability of cells to continue migrating along the radial glia to their final destinations is thought to be governed by microtubule function within the migrating cell. LISI and DCX are two genes that colocalize with microtubules and regulate microtubular cytoskeleton function. Mutations in these genes lead to cells derailing from the radial glia prematurely. Mutations in LISI cause type I lissencephaly and mutations in DCX lead to double-cortex syndrome.

Question 38

Describe the stage of Stopping Neuronal Migration in the cerebral cortex

Answer 38

Once cells have reached their destination, they need to be able to get off the radial glia scaffolding. Reelin (coded for by the reeler gene) is a large extracellular protein expressed by Cajal-Retzius cells in the marginal zone. Migrating cells have receptors (VIdIr and Apoer2) that bind to reelin, which signals them to stop migrating. Note that Dab1, an intracellular protein in migrating cells is important in transducing the reelin-receptor binding signal into migration termination. Reelin is also involved in development of the cerebellum. Defects in reelin lead to lissencephaly with cerebellar hypoplasia (LCH).

Question 39

Define radial migration.

Answer 39

Cells move out from the ventricular zone along radial glia that project out to the surface of the neural tube. This is the type of migration exhibited by the majority of the cerebral cortex and glutamate-containing neurons

Question 40

Define tangential migration.

Answer 40

Cells migrate tangentially from the ventricles. GABA-containing cells follow tangential migratory paths.

Question 41

Define chain migration.

Answer 41

Neurons move together in chains through the rostral migratory stream (a pathway for neurons moving from the subventricular zone to the olfactory bulbs.) Neurons of the olfactory bulbs demonstrate chain migration

Question 42

What neuronal populations do neural crest cells give rise to?

Answer 42

Neural crest cells gives rise to sensory ganglia, sympathetic neuroblasts, Schwann cells, pigment cells, odontoblasts, meninges, and the mesenchyme of the pharyngeal arches. Neural crest cells follow different migratory paths. One such path, the trunk path, gives rise to two streams of migrating neural crest called the ventral and dorsal stream. The dorsal stream gives rise to pigment cells. The ventral stream of neural crest moves under dorsal dermatomyotomes and gives rise to sensory, autonomic and enteric ganglia.

Question 43

List neurotrophins and their most common receptors

Answer 43

NGF > TrkA
BDNF > TrkB
NT3 > TrkC

• *Each neurotrophin can activate one or more receptor.
• *The major role of all of these neurotophins is to inhibit programmed cell death in developing neurons

Question 44

Long range axon guidance

Answer 44

Diffusible and create a gradient that can be attractive (induced growth towards) or repulsive (induces growth away).
Attractive: Netrins
Repulsive: Semaphorins and Netrins

Netrins can be both attractive and repulsive due to different receptor actions.

Question 45

Short range axon guidance

Answer 45

Short range signals are usually bound to cell the cell membranes of local cells or ECM and require direct cell-to-cell contact.

Attractive: Cadherins and CAMs on cell surface
Collagen, Laminin, Fibrinectin and Proteoglycans on ECM

Repulsive: Semaphorins and Ephrins on cell surface
Tenascin on ECM

Question 46

Are semaphorins long or short range guidance molecules?

Answer 46

Semaphorins can be long range or local depending on whether they are tethered to the membrane or if they are cleaved and secreted.