Lecture #4

Question 1

what is arealization and regionalization of the cerebral cortex?

Answer 1

a branch of developmental biology that investigates how the cerebral cortex can undergo such a complex regionalization

Question 2

what does arealization refer to?

Answer 2

the formation of the functional subdivisions of the neocortex during prenatal development

Question 3

which of the two neocortex formation hypothesis are correct?

Answer 3

probably both → basic regionalization is independent from extracortilal signals while the fine tuning of each individual area requires the presence of the fibers

Question 4

how is it possible that NECs undergo this arealization without any signals?

Answer 4

NEC regionalization was found to be dependent on the presence of specific signaling / patterning centers in the brain → specific areas of the developing cerebral cortex in which there are cells all to release in the extracellular space diffusible signals like proteins, hormones, etc.

Question 5

what are the three main patterning centers of the cortex?

Answer 5

cortical Hem, anti-hem, and anterior neural ridge

Question 6

describe the cortical hem patterning center:

Answer 6

in the medial and dorsal part

short piece of tissue at the boundary between the cortex and choroid plexus able to release into the surrounding tissues glycoproteins and general proteins with signaling cues

Question 7

describe the anti-hem patterning center:

Answer 7

located in the front of the hem - in the schematized vesicles it is in the lateral region, in the midline between the cortex and the ganglionic eminences

specialized cells release signaling factors producing a gradient of the molecules which has the peak of the concentration near the production site and is lower in distant sites

Question 8

cells in the anti-hem patterning center belong to what family and what do they secrete?

Answer 8

secreted frizzled related proteins (SFRPs) → role is to mimic the Int receptor called Frizzle

can bind Wnt in the extracellular spaced avoid the activation of this pathway in the surrounding cells counteracting its action (antagonist)

Question 9

describe the anterior neural ridge patterning center (ANR):

Answer 9

located in the frontal part of the brain

contains specialized cells that can release in the extracellular space proteins belonging to the family of FGFs such as FGF8 and FGF2

Question 10

where is the Hem located?

Answer 10

medial part of the telencephalon vesicles and in the dorsal half

Question 11

where is the anti-Hem located?

Answer 11

between the cortex and subcortical regions

Question 12

describe how each section of the cortex receives signals:

Answer 12

the NECs receive different signals and the intensity of the signals depends on the position

using these gradients we can shape the cortex, because the probability that signals arrive far from where they are produced is low, so the differentiation is specific and dependent on the signals

Question 13

what are the three parts of the cortex?

Answer 13

isocortex (neocortex) - 6 layers

allocortex - 3 layers

mesocortex: transition zone

Question 14

what are the two types of neurons in the cortex regions?

Answer 14

excitatory and inhibitory

Question 15

what does the inhibitory neuron system consist of?

Answer 15

consists of neurons releasing specific neurotransmitters whose function is to block the action of other neurons, providing the classical circuitry we have in the CNS

Question 16

what is the most common type of neuron in the cerebral cortex?

Answer 16

excitatory glutaminergic projection neurons, and a great portion are pyramidal, which extend axons to distant intra-cortical, subcortical, and sub-cerebral targets

Question 17

describe how a typically excitatory synapse works

Answer 17

there is a release of glutamate that can interact with the receptor in the post-synaptic membrane opening it

the activation of the neuron is mediated by the entrance of positive charges such as Na into the post-synaptic cleft which causes the depolarization of the membranes potential

Question 18

describe how inhibitory synapses work:

Answer 18

inhibition is possible through the entrance of Cl after the interaction of GABA (or sometimes glycine) released by the inhibitory neuron in the synaptic space, with the receptor on the post-synaptic membrane

Cl entry causes a hyper polarization of the membrane of the second neuron

Question 19

how are excitatory neurons generated?

Answer 19

asymmetric division of NECs → one daughter cell maintains the same phenotype conserving the ability to extend long cytoplasmic bundles that connect the cell body to the apical and basal membranes, and the other loses the connection and starts to acquire the features of a young neuroblast that moves from the germinal niche ad arrives in the regions in which the cortical brain will be formed

Question 20

after the initial decision, wha occurs during the second division of excitatory neurons?

Answer 20

a second divison occurring from radial glia cells descending from another one could generate a second cortical plate neuron = cpn2

Question 21

describe the “inside out rule” in regards to the generation of the cortical plate:

Answer 21

neurons generated very early during cerebral development are fat4ed to acquire the phenotype of deep cortical plate layers, while neurons generated later in the middle or end of corticogenesis are fated to acquire the phenotype of layer 1 or 2

Question 22

in which two areas of the brain are inhibitory neurons generated?

Answer 22

medial ganglionic eminences (MGEs) and the lateral ganglionic eminences (LGEs)

Question 23

how do NECs located in the MGE divide?

Answer 23

they divide in an asymmetrical manner like the cortical ones to give rise to young neuroblasts that start migrating in very long tangential journeys from the ventral half of the brain to the cerebral cortex

Question 24

what do the vast majority of inhibitory neurons express (70%)?

Answer 24

Parvalbumin - calcium binding protein

Question 25

what do Martinotti cells or basket cells express?

Answer 25

Somatostatin

Question 26

what do bipolar or double-bouquet cells express?

Answer 26

Vasointestinal peptide (VIP)

Question 27

where are virtually all of the inhibitory neurons generate?

Answer 27

outside of the cerebral cortex by asymmetrical cell division of the NECs present in the MGE or LGE

very few are generated in the pre-optic area in the deep thalamus

Question 28

what was discovered about the molecular mechanisms forcing these cells to reach their final position?

Answer 28

young neuroblasts are attracted thanks to signals like CXCL12, a chemokine expressed by specific cells in the cortex and are repelled due to signals like SemaA and Sema3F

if they sense CXCL12 it is sufficient to trigger their further migration

Question 29

what is the in utero electroporation (IUE) technology?

Answer 29

makes use of somatic transgenic embryos or mice and plasmids encoding the GFP

a specific electroporator can produce a square wave electric field that can help us measure the brain for GFP (that was injected) to see the amount of cells expressing it and track their movement

Question 30

from the MGE and the POA, what TFs were discovered that have been found to be expressed in regions where the cortical GABAergic neurons arise

Answer 30

Nkx2, Mash1, Dlx1/2, and Lhx6

Question 31

what was Nkx2 characterized as?

Answer 31

a key TF for inhibitory neurons migration

Question 32

in humans, where do a large of inhibitory neurons originate from?

Answer 32

not from the ventral half of the brain, but from the NECs in the cerebral cortex

Question 33

what was the Reeler mutant phenotype characterized by?

Answer 33

the loss of the inside out sequence of neuronal migration involving excitory neurons

Question 34

what is Reelin?

Answer 34

a big secreted protein belonging to the family of EGF domain proteins released by neurons in layer 1 (marginal zone)

Question 35

what are the neurons in layer 1?

Answer 35

Cajal-Retzius (CR) neurons and they can release Reelin into th marginal zone

Question 36

what happens when migrating neurons enter in contact with reelin?

Answer 36

the interaction of reelin with its own receptors VLDR ad ApoER2 induces the activation of Dab1 cascade in the cytoplasm that ends up with the detachment of neurons from the radial glia cells inducing the conclusion of migration

Question 37

what occurs in the absence of reelin?

Answer 37

neurons are not able to conclude the migration resulting in a packed and inverted cortical plate

Question 38

list some reasons why there may be disorders in the cortical plate:

Answer 38

• malformation that could involve the proliferation of neuroepithelial cells
• decreased proliferation or increased cell death = microencephaly
• increased proliferation or decreased apoptosis = megaencephaly
• malformation deriving from aberrant migration of neurons
• malformation involving other defects in the initial development of the cerebral cortex

Question 39

what do defects in radial migration of young neuroblasts induce?

Answer 39

a severe and intractable epilepsy as well as severe cortical malformation associated with mental retardation

Question 40

what is Filamin1 and what occurs in its absence?

Answer 40

a protein associated with actin and cell morphology

in its absence the cortical malformation is called periventricular nodular heterotopia

neurons generated by asymmetry cell division from neuroepithelial cells cannot migrate and start to accumulate above the germinal niche never reaching the cortical plate

Question 41

what occurs in most disorders involving the aberrant migration of neurons?

Answer 41

the genesis of the corpus callosum

neurons in layers 2-3 in the cortical hemisphere connect with other cortical neurons sending their axons from the lamina t the other cortical neurons located in the other hemispheres

Question 42

what is the callosal commissure?

Answer 42

a wide thick nerve tract consisting of a flat bundle of commissural fibers beneath the cerebral cortex of the brain

Question 43

what occurs in holoprosencephaly?

Answer 43

incomplete separation of the two hemispheres, so in the midline there is not the closure of the individual telencephalic hemispheres

Question 44

what does the holopresencephaly phenotype usually derive from?

Answer 44

teratogens such as alcohol

Question 45

what is tuberous sclerosis complex syndrome?

Answer 45

frequent pediatric disorder deriving from the inactivation of the TSG genes 1-2

affects the brain with the formation of tuberous accumulation of neurons in the ventricular cavity (in newborns has a potato shape)

Question 46

what is. key complex in cell proliferation and homeostasis?

Answer 46

mTORC1 complex → very important for its ability to regulate cell proliferation and overall autophagy

Question 47

what does blocking mTORC1 result in?

Answer 47

induction of autophagy

Question 48

how are TSC1/2 and mTORC1 related?

Answer 48

TSC1/2 genes are indirect regulators of mTORC1 and they are regulated by a multiprotein kinase AMPK (a sensor of the levels of AMP in the cell)

in the case of too much AMP AMPK induces the phosphorylation of the two TSC complexes blocking Rheb (an activator of the mTORC1 complex)

autophagy is induced

Question 49

describe the potential disorders due to abnormal cortical migration:

Answer 49

• disorders occurring at the onset of migration
• disorder of the ongoing process of migration
• problems in penetration of the subplate
• disruption of the architecture of the developing cerebral wall

Question 50

what is Miller-Dieker syndrome?

Answer 50

a pediatric disorder characterized by the lack of LIS1, an x-lined gene involved in the migration of neuroblasts so causing severe lissencephaly

Question 51

what is teratology?

Answer 51

the branch of human embryology and pathology studying reasons behind malformations of the brain

Question 52

what are the three types of trisomy?

Answer 52

13 (Patau), 18 (Edwards), 21 (Down syndrome)

13+18 are not compatible with life