NB3-3 - Neurodevelopment DLAs

Question 1

From what germ layer does the neural plate develop? How does this happen?

Answer 1

From the ectoderm. During early development, BMP (bone morphogenic protein) is released by cells of the ectoderm ensure they remain ectodermal cells. At some point, the cells in the midline begin releasing Chordin and Noggin which counteracts BPM and those cells differentiate into the neuroectodermal cells, forming the neural plate.

Question 2

When does the neural groove begin to develop? How many times must the neuroectoderm divide to fully form the neural tube?

Answer 2

The neural groove begins to develop at 20 days and the neuroectodermal cells do NOT divide to form the groove. They just change shape.

Question 3

List the structures derived from the neural tube and neural crest cells.

Answer 3

Neural Tube Derivatives - brain, spinal cord, motor neurons, retina

Neural Crest Derivatives - adrenal medulla, melanocytes, dorsal ganglion, schwann cells, SNS & PSNS, sensory neurons

Question 4

What occurs if the neuropore fails to close during development?

Answer 4

Failure of the rostral neuropore to close leads to Encephaloceles

Failure of the caudal neuropore to close leads to Spina Bifidas

Question 5

What is an encephalocele?

Answer 5

It is a protrusion of a sac from the cranium consisting of portions of the meninges, CSF, glial tissue, and brain substance with or without the ventricles

Question 6

What is another name for Spina Bifida? Describe the different types of spina bifida

Answer 6

• Spina Bifida is aka Myeloschisis and there are two general types:
  
  • Spina Bifida Occulta (CNS contents do not protrude) - usually caused by a mesodermal malformation (usually with the vertebra). There are often no neurological defects. A tuft of hair does appear on the skin though.
  • Spina Bifida Aperta (CNS contents do protrude) - two types
    
    • Meningocele - just the dura, arachnoid, and subarachnoid space protrude
    • Meningomyelocele - meninges and spinal cord protrude

Question 7

How are neural tube defects typically tested for?

Answer 7

Blood test markers - if AFP and AChesterase levels are high, this indicates possible neural tube defects and a follow up ultrasound would be done.

Question 8

What are the primary and secondary vesicles associated with brain development? What drives the maturation from primary to secondary?

Answer 8

The primary vesicles are the prosencephalon (forebrain), mesencephalon (midbrain), and rhobencephalon (hindbrain). After segmentation, the prosencephalon is separated into the telencephalon (and optic vesicles) and diencephalon, the mesencephalon remains, and the rhombencephalon is divided into the metencephalon and myelencephalon.

This segmentation is driven by differential gene expression in the cells.

Question 9

What are neurotrophins? List the ones we need to know and what they do. Where do these neurotrophins come from?

Answer 9

Neurotrophins are a family of growth factors required for nervous system development. There are two major kinds:

Nerve Growth Factor (NGF) - stimulates growth of sensory and sympathetic neurons in the PNS during early development

Brain Derived Neurotrophic Factor (BDNF) - help to stimulate neuronal growth within the brain itself

Early in development, neurotrophins are provided by the neurons themselves and by the mesenchymal tissues through which the axons grow. Later, after the axons reach their targets, sensory neurons begin to express NGF receptors and become dependent on target-derived NGF.

Question 10

What are the genes called that regulate development of anatomical structures? List the ones we need to know and what they do.

Answer 10

Homeotic Genes

• Emx & Otx lead to telencephalon development
• Pax6 leads to eye and diencephalon development
• Otx leads to mesencephalon development
• Hox leads to met- and myelencephalon development

Question 11

What is the abnormality often seen when there are Emx genetic defects?

Answer 11

Schizencephaly which is a rare congenital malformation of the cortex where the sulci and other parts of the cortex may be absent or replaced with CSF.

Question 12

What causes homeotic gene activation?

Answer 12

The retinoic acid gradient along the longitudinal axis of the developing brain. Retinoic acid is produced by Hensen’s node.

Question 13

Describe what rhombomeres are the cranial nerves that are associated with them.

Answer 13

In the rhombencephalon, the process of segmentation is particularly evident. It contains many neuronal subtypes and nuclei that organized into 8 distinct modules called rhombomeres.

Rh2 - trigeminal nerve (V)

Rh4 - facial nerve (VII)

Rh6 - glossopharyngeal (IX)

Question 14

Describe what drives the formation of the alar and basal plates?

Answer 14

BMP 4 & 7 are released by the ectoderm and it drives the dorsal aspect of the neural tube to develop alar plates

The notochord releases sonic hedgehog (SHH) protein which drives the ventral aspect of the neural tube to develop basal plates

Question 15

Answer 15

Question 16

Describe how axonal growth is guided within the spinal cord.

Answer 16

Netrin, produced by the floor plate, guides axonal growth in the developing spinal cord. It will attract the axon towards the floor plate in the midline of the spinal cord. Once it nears the midline, the floor plate will begin releasing Slit which will push the axon away from the midline to the other side of the cord. This is how axons cross-over and/or exit the spinal cord

Question 17

What is holoprosencephaly and its symptoms?

Answer 17

It is a failure of the telencephalon to separate into a right and left hemisphere which can ofter present with a cleft palate and/or cyclopia.

Question 18

Answer 18

A

Question 19

What is PMP-22 and what does it do? What pathology most commonly affects this compound and what are the symptoms? When do these symptoms typically appear?

Answer 19

Periperal Myelin Protein 22 (PMP-22) is a protein secreted by schwann cells that is essential to the process of layering schwann cell membrane as myelin.

A single AA substituion (gly to asp) in the PMP-22 gene leads to Charcot Marie Tooth disease in humans which is a peripheral neuropathy characterized by limb weakness due to muscle atrophy and defects in both gross and fine motor movements. Is not fatal

Symptoms appear late in childhood or in adulthood

Question 20

Describe the importance of apoptosis to the neuronal development of lower motor neurons.

Answer 20

In early development, muscle fibers receive polyneural innervation which is inefficient. Later on, muscle fiber activity and trophic factors from muscle and glial cells will cause lower motor neurons to undergo apoptosis until only a single neuron is innervating a muscle fiber (aka mononeural innervation)

Question 21

What typically causes neuronal apoptosis during development?

Answer 21

Failure to compete for chemicals produced by targets

Question 22

Describe which retinal fibers go to which side of the occipital cortex and which layer.

Answer 22

Fibers from the left side of the retina in both eyes (so those regions that receive light from the right side of your visual focus) will go to layer 4 of the left occipital lobe

Fibers from the right side of the retina in both eyes (so those regions that receive light from the left side of your visual focus) will go to layer 4 of the right occipital lobe

Question 23

Describe what the critical period in visual system development is.

Answer 23

At birth, neurons from the right and left eyes overlap in the occipital lobe. This is ineffecient. As human development continues, and the eyes are exposed to more visual stimuli, synapse apoptosis (pruning) occurs so that right and left fibers no longer overlap and they segregate into descrete clusters which are called ocular dominance columns. This period of “pruning” is the critical period in visual systems because it can only occur in the first 6 weeks of life and if it doesnt occur properly then vision problems can arise.