Brain Embryology

Question 1

What is the oldest way of looking at the brain in terms of development?

Answer 1

pathology (i.e. preforming surgery on the brain postmortem to see the problem)
- in development, its looking at the anatomy at different stages of development using pathology (i.e. obtaining brain slices at different stages of development)

Question 2

How can neuroimaging be used to look at brain development?

Answer 2

MRI gives precise picture of the brain and can also be taken in utero to observe the child’s brain and heart developing in the womb

Question 3

What is the main difference between looking at the brain in development with pathology and MRI vs. looking at it through genetics?

Answer 3

pathology and MRI tells us what happens to the brain development, while genetics is useful to understand what CAUSES the normal/abnormal development

Question 4

What are some ways that genetics can be used to understand normal and abnormal development?

Answer 4

1. through karyotypes which are compacted chromosomes; different bands on chromosomes absorb a color of dye added to it, we look at genetic diseases via looking at matching bands
2. when the defects are past the karyotype level then we use the genome wide approach which is a chip that allows you to look at DNA in more details
3. Comparative genomic hybridization –> using the WBC of patient to compare to the DNA of control (normal) subjects to see if the patient has deletion of duplication. You mix the control color (i.e. green) with the patient color (i.e. red) and see if it will produce yellow, if it produces RED, it means that the patient has a duplicate, if it produces GREEN it means that patient lacks this gene therefore its a deletion; the next thing to do is check family tree for any known deletion

Question 5

What are the 7 developmental events that occur in brain embryology? and when do they occur

Answer 5

1. Gastrulation (15 days)
2. Primary Neurulation (3 weeks)
3. Prosencephalic development (2-3 months)
4. Neuronal proliferation (3-4 months)
5. Neuronal Migration (3-5 months)
6. Organization (3 months and beyond)
7. Myelination (birth to adult)

Question 6

What happens during gastrulation?

Answer 6

• first 15 days
• 3 layers of cell form: endoderm, mesoderm and ectoderm. The ectoderm is the neurons and skin
  1. the first 6 days after conception, the hypoblast forms
  2. on day 8, two layers form: the epiblast and hypoblast
  3. the epiblast opens up (it creates a cavity) and inside the cavity is where the migrating cells that form the mesoderm are
• the formed mesoderm gives rise to the notochord which is a transient structure (temporary) formed by the mesoderm that will affect the development of ectoderm (the skin and neurons)

Question 7

What happens during primary neurulation?

Answer 7

• first 3 weeks
• neurulation refers to the formation of the neural tube from a flat layer of ectodermal cells (starts with a sheet of cells and it starts to bend into a tube) the tube is the precursor for the spinal cord and brain

Question 8

what are the important genes involved in the molecular signaling of neurulation? draw this

Answer 8

TGF-beta
BMP
Sonic hedgehog
- some genes are expressed in dorsal aspect (from the ectoderm) and some in ventral (from the notochord)
SHH is secreted initially from the notochord

Question 9

How are somites formed in Neurulation phase? Which gene is responsible for the regulation of somites?

Answer 9

somites will form the cartilage of the vertebrae and ribs, muscle of the rib cage, back, limb dermis of the dorsal skin… gene hairy is responsible for the regulation of somites

Question 10

When does the neural tube close at the end of neurulation?

Answer 10

• needs to close to not have connection of CNS to the outside environment;
• anterior neural pore closes in 24-26 days and the posterior pore closes in 25-28 days
  multiple segments close at different times and they close usually before a month after fertilization

Question 11

What it is anencephaly and spina bifida?

Answer 11

• both conditions when anterior neuropore doesnt close properly (anencephaly) and posterior neuropore doesnt close properly (spina bifida)
  both during the neurulation stage

Question 12

What occurs in the prosencephalic development?

Answer 12

2-3 months in development

• the anterior part of the neural tube splits into 2 prosencephalic vesicles (which end up being the two hemispheres of the brain)
• after 19 days, the three primary brain vesicles: forebrain, midbrain and hindbrain start bulging from the tube
• after 33 days: the telencephalon can be seen (split into two parts) and the diencephalon, mesencephalon, metencephalon and mylencephalon are distinctly bulging out

Question 13

What is holoprosencephaly? What are the genes known to be associated with this?

Answer 13

its the failure of cleavage of the 2 hemispheres resulting in one big lump and the brain structures that are normally seperated are lumped together

• genes associated with holoprosencephaly is the SHH sonic hedgehod pathway
• the SHH pathway involves patched and smoothened receptors and a second messenger called GLI that results in the transcription of DNA and proliferation (more number of cell growth)

Question 14

What else forms around 2 weeks of gestation?

Answer 14

the formation of the brain stem which regulates breathing and heart rate

Question 15

What is Mobius syndrome? What is it the disease of? and what causes it?

Answer 15

it is a congential partial or complete facial diplegia (facial nerve palsy), that involves damage in the cranial nerves for the eyes 6th and 3rd
- and malformation of the limbs called equinovarus (fused fingers)

this is a disease of brainstem development caused by hoxb-1 and hoxb-4 genes during development

Question 16

What occurs at the neuronal proliferation stage?

Answer 16

• at 3-4 months

- the brain is thicker than a tube therefore there needs to be rapid cell growth (proliferation)

Question 17

What happens when neuronal proliferation is excessive?

Answer 17

a condition called hemi-megalencephaly … when one hemisphere is bigger than the other
- the bigger hemisphere represents an excess in proliferation

Question 18

What occurs when the excess cells produced in neuronal proliferation are abnormal (cancerous/tumour)?

Answer 18

a disease called tuberous sclerosis (skin and brain disease)
- is associated with mutations in the tuberous sclerosis genes TSC1 and TSC2 and is associated with intellectual disability, epilepsy and autism

it is when subpendymal giant cell astrocytoma (SEGA) are present in 6-14% of patients that is tumour near their ventricle and causes TS and can cause death

Question 19

What occurs when theres lack of neuronal proliferation? (not enough cell replication)

Answer 19

it leads to a disease called microcephaly (small head)

• and acquired microcephaly is when the patient’s head is normal upon birth but starts to grow LESS after birth and fails to progress normally
• they use a graph to measure head circumference of the patient compared to his/her parents to see if its a genetic abnormality that runs in the family (normal) or if its abnormal

Question 20

What are the genes involved in telencephalon proliferation? What genes are lacking or mutated in individuals with microcephaly?

Answer 20

the genes involved include:
growth factor FGF8 and its action on FOXG1
- also the action of SHH and wingless and BMP4
- theres also a component of apoptosis (programmed cell death)
- therefore microcephaly in FOXG1 mutant is due to both excess apoptosis and lack of maintenance in cell proliferation (maintenance of FOXG1)

Question 21

What major events occur during neuronal migration?`

Answer 21

• 3 to 5 months
• the human cortex is formed and organized into 6 layers of neurons
• the cortical plate (CP) area of the layers of the cortex contains barely any neurons in newborns but starts filling up with neurons as individual gets older

Question 22

What is inside-out migration?

Answer 22

its the formation of the layers where the neurons are born in the periventricular zone and then migrate out towards the brain’s surface along the help of progenitor cells which then turn into glia cells (inside out bc it starts at inside of brain and reaches the brain surface)

Question 23

What occurs during defective neuronal migration?

Answer 23

neurons stays close to the ventricles and do not migrate to surface.
- a condition called periventricular nodular heterotopia occurs when patients suffer from epilepsy and cognitive dysfunction because of genetic mutation

noted conditions called: Filamin I (X), ARFGEF 2 (20q), Elastin (williams syndrome) and fragile x syndrome
are seen when theres defective neuronal migration.

more common in boys

Question 24

What is Lissencephaly?

Answer 24

it means that the brain lacks bumps and gyrus upon birth and contains a smooth brain (causes abnormal migration of cells to brain surface)

Question 25

What are some genes associated with lissencephaly?

Answer 25

• LIS I
• 14-3-3 varepsilon
• doublecortin
• Reelin
• ARX

Question 26

What are the major events that occur during the organization stage?

Answer 26

• at 5 months and beyond
• subplate zone forms –> the subplate is the temporary layer of neurons that underlie the future development of cortical neurons
• if SP is disrupted then connections in the brain are altered as well (i.e. like connecting the brain cells to visual cortex)
• once the necessary cortex regions are formed, then the SP cells will dissapear
• alot of intellectual disabilities and autism disorders are thought to be because of abnormal organization of neocortex and problems w the way connections are made

Question 27

What is neurite outgrowth?

Answer 27

its dendrites and axons develop over time leading to an increas ein the neuron arborization (fine branching at the end of the nerve fiber) and these branches are crucial for making connections

Question 28

What occurs during spine development (dendritic spines)?

Answer 28

synapses are formed at the tip of the dendrites on a structure called the spine

• long spines are immature and short stubby (mushroom shaped) spines are mature spines
• the shape of the spine effects its function

Question 29

What are 5 diseases that involved or occur due to abnormal dendritic arbor/spines?

Answer 29

1. mental retardation with or w/o seizure
2. down syndrome
3. fragile X syndrome
4. angelman syndrome
5. autism

Question 30

What is fragile X syndrome

Answer 30

• most common intellectual disability in males
• includes some dysmorphic features
• heavily connected with autism (60%) and epilepsy (30%)
  caused by mutation in the fragile X gene leading to absence of fragile X protein
• studies done on flies, mice and humans show that ppl with fragile X had excess long thin dendritic spines (immature ones) and theres also a memory defect linked to fragile X

note: when learning something, immature spines will form into a bud shape and stay that way (mature), but in ppl with fragile X, that doesnt occur

Question 31

How does the glia proliferate and what does it do?

Answer 31

• it transforms from guide cells into glia
• recycles glutamate into glutamine (not usable form)
• regulates calcium flux in neurons (cell depolarization regulation)

Question 32

What occurs in the last stage of development, myelination?

Answer 32

• birth and beyond
• myelin forms to allow for saltatory conduction (quick conduction and processing of information) and it increases speed of synaptic connections and cell communication
• myelin progressively develops with age as neonates have virtually no myelin and by the time they’re 19months old they have alot of white matter forming (and their integration of signals increases)