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Mechanism Of Brain Development > Prof Andrew Jarman > Flashcards

Prof Andrew Jarman Flashcards

1
Q

What is the name of the binding accessory which stabilise the array of microtubules in an axon? Name this binding accessory that is specific to dendrites and axons.

A

Microtubule-associated protein (MAP) and Tau

Dendrites: MAP2

Axon: MAP1B and Tau

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2
Q

State the mechanism in which axon elongates

A

Elongation occurs not by stretching because the microtubules are rigid, instead they laid out new membrane components to elongate themselves.

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3
Q

In the Ena/VASP mutation, what was the observation? And which structure is affected?

A

The mutant cannot formed lamellipodia and does not seem to exhibit actin dynamics. ENA/VASP protein are known to be involved in actin polymerization and chemotaxis of the lamellipodia.

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4
Q

Describe the six stages of neurite outgrowth

A
  1. Neural precursor cells is spherical. The mesh-work of actin filaments under its plasma membrane act as a barrier and prevent the formation of outgrowth.
  2. Actin filament is disrupted at specific points -> allows penetration of microtubules -> formation of lamellipodia and filopodia
  3. The initial sprouts are very dynamic -> initial sprouts is formed but is still very much dynamic
  4. Cells becomes polarised: one become the dendrites and one become the axon
  5. Remaining neurites stopped their cycles of being ‘dynamic’ and develop into branches or mature into dendrites.
  6. Neutrons established their identity by its morphology (some develop dendritic spines)
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5
Q

What protein in laminin? Which process does it involves in?

What is CSPG?

A

Laminin is a complex protein with multiple domains that binds to other proteins in the ECM and on cells and axons. It is a potent inducer of neurite outgrowth.

CSPG inhibit laminin-induced outgrowth of cultured cells.

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6
Q

Name two mechanisms which is required for the formation of filopodia and lamellipodia. And how do they able to achieve this?

A

Cytoskeleton rearrangements and recruitment of new membrane components to the growing site. Through complex network of signalling molecules and second messengers

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7
Q

What is the name of the two factors that could switch between the inactive and active state of small G proteins?

A

GEF - guanine nucleotide exchange factor, swap bound GDP to GTP causing activation

GAP - GTPase activating protein, promote G-protein catalysed hydrolysis thereby causing inactivation of G protein

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8
Q

List the members of the Ras superfamily and what do each members of the family regulate?

A

Rho, Rac and Cdc42

This superfamily is involved in cell shape regulation, activating gene expression and promote neural survival and plasticity.

Rho: inhibit axon elongation
Rac: promotes axon elongation
Cdc42: initial outgrowth and neurite branching

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9
Q

what set up the pattern of gene expression?

A

morphogen

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10
Q

what is the 15 segmental units in the insect nervous system?

A

ganglia

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11
Q

which comes first? diversification or segmentation of neurones?

A

diversification

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12
Q

at the syncytial blastoderm stage, are the cells identical to each other?

A

cells look morphologically identical but they are already expressing different genes. EVEN BEFORE GASTRULATION AND NEURAL INDUCTION OCCUR

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13
Q

what does the French flag model demonstrate?

A

it demonstrate that molecules respond to different morphogen concentrations and the response is activation of inhibition of gene expression

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14
Q

which axis does the bicoid and hunchback diffuse through?

A

anterior to posterior

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15
Q

what do bicoid and hunchback activate and how to they do it? what do you refer to this molecule which can induce gene activation in a certain manner?

A

gap genes in threshold dependent manner

morphogens

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16
Q

where in the embryo does hb regulate the expression of kr?

A

in the middle of the embryo

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17
Q

how does the expression of gap genes later established a distinct and sharp domain?

A

example: kruppel and giant

kr and gt have repressive interactions this helps to sharpen their expression boundaries

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18
Q

what do gap genes encode?

A

zinc finger TF

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19
Q

how is the AP identity of cells established?

A

through the combination of gap and pair-rule genes which activates hox genes in different AP domains.

therefore different segments express different combinations of hox genes -> identity

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20
Q

what do the hox genes encode? and how do these genes arose?

A

the encode homeodomain TF

tandem duplication

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21
Q

what is the homeotic effect?

A

mutation which causes one body part to resemble another (Ubx mutant has additional wings in different segment)

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22
Q

which structure has segments called rhombomeres?

A

hindbrain

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23
Q

we know in drosophila hox genes are important in patterning the AP axis, what about in vertebrates?

how is the what hox genes regulate differ in both drosophila and vertebrates?

A

pattern this hindbrain and SC

e.g. rhobomeres (segments)

in drosophila the mutations are simpler but in vertebrates mutations of different regions in rhombomeres causes more complex phenotype hence, hox genes also plays a role in segmentation in addition to segment identity

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24
Q

what are the fours early graded signals which regulates the hox genes? which ones are the posterirorizing signals?

A
  • BMP
  • Wnt
  • FGF
  • Retinoic acid

last three are posteriorizing signals

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25
name the signal which sets a default anterior fate of the neural plate
BMP inhibitors
26
later graded signals are posteriorising signals how do the neural plate maintain its anterior identity?
through a third signal (extreme anterior) called cerberus (Wnt/FGF inhibitors)
27
what is retinoid acid? how does RA regulate the expression of Hox genes?
RA is a small organic molecule related to vitamin A it crosses the membrane of the recipient cell where it forms a complex with RA receptor (RAR). the RA-RAR complex translocates into the nucleus where it target genes by binding to DNA sequence called retinoid acid response element (RARE). Thus regulate the expression of some hox genes
28
is hox genes expressed in the anterior brain?
NUUUUUU. anterior brain referring to forebrain/midbrain. but they are expressed in the hindbrain -> SC
29
name the six genes which gives each segment of the brain its identity and pair them with the ones they formed boundaries with
Six3 -> Irx3 Pax6 -> En1 Otx2 -> Gbx2
30
where do neuroblasts gain their identity from?
from their location
31
what gave rise to two new signals being produces in the AP of each segment in Drosophila? what happened after this?
interactions of TF between the AP cells give rise to expression of wg and hh mRNA. the mRNA translates into protein which creates a local gradient
32
what gives neuroblasts its unique individual identity?
intersections expression of genes
33
how do new signalling centres formed?
they formed at boundaries between gene expression for local patterning
34
where is the isthmic organiser located and what does it expressed? what structure develop and a result of this patterning?
boundary between midbrain and hindbrain FGF8 and Wnt1 which diffuses locally through the midbrain (FGF8). in which it activates TF encoded by en1 and en2 -> formation of the cerebellum and tectum
35
remember the irx3, six3, etc are genes that creates and set BOUNDARIES and THEY ARE TF GENESSSSS
Otay.
36
what are the three features of morphogen (in terms of how they affect the cells)?
1. they formed a concentration gradient 2. induce activation or inhibition of gene expression in cells that respond to it 3. they provide positional information
37
what is homeotic transformation? give an example and what do they conclude when the observed mutation in the Hox gene causes homeotic transformations in segment identity?
homeotic transformation is when the mutation of a hox gene causes the mutated segment to resembled the identity of another segment. mutation in Ubx (ultrabithorax) gene causes the third segment to develop as if it has the identity of the second thoracic segment. therefore the normal function of Hox gene is t assigned identity to a segment, selector genes
38
what do columnar genes encode?
homeodomain transcription factors
39
where do neuroblasts gain their identity from?
from their location (remember the interesting expression of AP and DV TF)
40
what are the two signals being produced that is responsible in local AP patterning in drosophila and how does this occurred?
WG: wingless HH: hedgehog interactions between A and P cells lead to these two new signals being produced and formed a diffusible gradient
41
what are the two signal proteins with opposing activity that formed a morphogen gradients important in patterning the AP axis in DROSOPHILA?
dorsal: DPP ventral: dorsal, a TF for ventral pattern
42
which type of gene does dorsal and DPP activate?
they both activate the columnar genes in drosophila. the columnar genes respond to different levels of DPP and dorsal
43
therefore segmentation genes gives neuroblasts their ....(1) location and columnar genes give neuroblasts ....(2) location in Drosophila
1. AP | 2. DV
44
in the neuronal patterning in VERTEBRATE NEURAL TUBE, where does the signal come from that is responsible for local AP patterning and DV patterning?
AP patterning: signal comes from interaction at boundaries between rhombomeres and anterior brain region
45
in vertebrates neural tube, what is the name of the group of cells which forms signalling centre at the boundary between midbrain and hindbrain? what genes does this signalling cells induced and what does it form?
isthmic organiser induces the expression of gene En1/En2 which code for TF En1 -> midbrain -> tectum En2 -> hindbrain -> cerebellum
46
which cells in the neural plate becomes the neural crest cells?
lateral cells of the neural plate
47
in vertebrates neural tube what give rise to distinct type of neurones?
the progenitor domains established at different DV levels
48
which part (layer) of the embryo is important for neural induction? why is this so?
underlying mesoderm signalling from the underlying notochord is important in patterning the neural tube
49
what is the ventral signal from the notochord that is important in defining the identity of the ventral midline?
notochord which produces SHH
50
describe the hedgehog signalling pathway
1. receptor of HH, patched inhibit smoothened 2. when HH binds, patched is downregulated and smoothened no longer inhibited 3. smoothened translocate to the membrane surface where it inhibits the cleaving of GLI (smoothened is a GLI activator) 4. GLI translocate to the nucleus where it exert an effect of modulating gene expression by binding to the double helix.
51
in vertebrates neural tube, which induces the floor plate and which induces the roof plate?
floor: SHH by the underlying notochord roof: induced by BMP
52
low[SHH] induces which type of neuronal fate? medium[SHH] .. high[SHH] ..
low: Vo and V1 mid: V2 high: MN and V3
53
SHH is important in DV patterning in
vertebrates only.
54
what is the type of gene does SHH induce in neural tube? how does the progenitor domain determined from this?
it induces homeodomain TF combination of gene expressed in each domain is a homeodomain code for the progenitor domain
55
what gives rise to the different identities of motor neurone in the AP axis? what give rise to the formation of motor neurones ventrally throughout the neural tube?
1. Hox genes | 2. Nkx genes
56
what controls neural subtype determination?
spatial and temporal mechanisms
57
what are the three aspects that differ axons and dendrites?
morphology, function and molecular structure
58
does microtubule have polarity?
yes
59
subunit of actin filaments subunit of microtubules what happened to the dynamic of these cytoskeleton in mature neuritis?
actin subunits alpha/beta subunits they are stabilised
60
what are the aspects that differ dendrites from axons?
microtubules in dendrites are not so well aligned | have different MAPs which can be use as a marker to differentiate dendrites and axons
61
describe how axons grow
1. they are rigid structure therefore extension occurs by addition of new cellular components instead of stretching out 2. the building block for the membrane addition is transported from the cell body into the growth cone
62
what happens when the growth cone senses favourable growth cues?
1. actin will capture one of the microtubules extensions (microtubule capture) 2. actin filament that captures the microtubule would extend hence pushing the microtubule towards the direction of the cue
63
what happened during acquisition of polarity in immature neurites?
an axon emerges and the rest produce branches and spines - dendrites
64
name the extracellular signals that influence outgrowth: 1. diffusible signals 2. ECM
1. Wnt, growth factors (e.g. neurotrophic), SHH | 2. laminin, proteoglycans and collagen, etc
65
what was observed when rat neural crest cell line was grown on laminin and laminin and CSPG-coated surface?
laminin: differentiate into neurones with outgrowth forming CSPG-laminin: cannot form axon outgrowth
66
how do signals influence outgrowth?
1. bind to receptors on the surface of growth cone which triggers intracellular signal transduction 2. leads to cellular responses such as changes in cytoskeleton structure and dynamics
67
explain the ENA/VASP mutant phenotype.
ENA/VASP required for actin dynamics (formation of filopodia and lamellipodia) -> disruption of dynamics -> cannot grow filopodia
68
what is the underlying principle which induces the expression of specific proneural genes in the development of vertebrates CNS?
BMP and SHH induces the expression of homeodomain TFs across the DV axis. the overlapping expression of these transcription factors (e.g. Pax7, Nkx6.1, Nkx2.2) create unique combinations which define different progenitor DOMAINS and in turn, this induces the expression of proneural genes such as Atoh1, Ascl1 and Neurog1
69
explain briefly what is lateral inhibition
it is a mechanism to ensure only one neural cells from the proneural clusters takes the step from competence to commitment this involves the Notch signalling pathway
70
what is the role of Atoh1 gene?
make cells competent to become a particular cell types e.g. sensory hair cells in Drosophila
71
which gene expression is UPREGULATED in committed cells?
proneural gene expression
72
which type of division does radial glial cell undergoes?
asymmetric division to produce different neural subtypes
73
which bHLH + HD factors activate Ascl1 and Neurog1?
Ascl1: Pax7 Neurog1: Pax6 + Nkx6.1
74
radial glia in the pMN produces
a mixture of neurons and glia
75
in the pMN progenitor domain: first born cells differentiate as ...(1) later born cells differentiate as ...(2)
1. motor neurons | 2. glial cells
76
what happened when a single isolated progenitor cell is cultured in vivo? what does this mean?
they produce several different neural cell types, therefore they are multipotent stem cells
77
apart from unique combination of patterning and proneural factors what else affect neural subtype differentiation?
birth date
78
name a mechanism in which neurons in the drosophila embryo can be arranged spatially and name which structure in the human adopted similar mechanism
arrange according to their birth date formation of the cerebral cortex layers (laminae)
79
what is the mechanism adopted by the ganglion mother cell to produce different neuron cells over time?
by expressing different TF at different times.
80
describe how the cortical laminae are formed
they are formed in an inside-out manner overtime 1. cells are born from the subventricular zone - the deepest layer 2. early born cells innervate the deeper layers first 3. later born cells migrate to innervate the superficial plial surface remember the progenitor cells are also radial glial cells
81
what does proneural genes trigger?
NEURAL DIFFERENTIATION
82
what is heterochronic transplant?
transplantation of old neural stem cells to young niche
83
what does svp regulate in drosophila? its vertebrate homologue in mouse retina
svp regulate Hb involved in differentiation of mother ganglion cell svp homologue is coup-tfl
84
describe how small g proteins Rac act as a molecular switch
1. when positive signal is received from the growth cone, receptor activation lead to activation of guanine nucleotide exchange factor (GEF) 2. GEF displaces GDP initially attach to Rac to GTP which results in activation of Rac 3. Rac-GTP binds to other proteins that modulate cytoskeletal stability 4. some receptor activation leads to the switching back of Rac to its inactive state 5. this is done by activation of GTPase activating protein which dephorphorylate GTP to GDP, inactivating Rac
85
in control of cytoskeleton dynamics, +ve signal activates .. (1a), responsible in ..,(1b) -ve signal activated ..(2a) and ..(2b) Rac and Rho ..(3) one another growth factor activates ..(4)
1a. Rac - 1b. axon elongation 2a. Rho 2b. CDC42 3. inhibits 4. Ras
86
what is the name of the signalling molecule activated by Ras? what does it involve in? what does cdc42 involve in?
PIP3, elongation cdc42 -> initial outgrowth (of filopodia and lamellipodia) and branching
87
what molecule does small g protein regulate? name them and their effects
regulate effector proteins which remodel cytoskeleton 1. Arp2/3 complex - promote nucleation of new actin filament hence branching 2. cofilin - promotes severing of actin filaments creating more barbed ends for EXTENSION
88
which signalling pathway is required for neuronal polarity? and describe this pathway
PIP3 signalling pathway 1. growth factor activates small g protein Ras which activates the enzyme PI3K. 2. PI3K phosphorylates second messenger membrane-bound PIP2 to PIP3. 3. PIP3 activates Akt and inhibits GSK-3beta which promotes microtubule stabilisation
89
which artificial microtubule stabilisation can trigger axon specification?
taxol and laminin
90
name the extracellular signals present in vivo which triggers axon specification
neurotrophin 3 which activates PIP3 -> microtubule stabilisation
91
name the possible mechanism which causes the formation of only one axon
microtubule stabilisation lead to enhance transport of more PIP3 into the particular neurite -> rapid elongation of neurite as axon -> other neurites straved of PIP3 form the cell body
92
name the MAPs present in axon and dendrites
axon: MAP1B and Tau dendrites: MAP2
93
name the small g proteins involved in the outgrowth of dendrites
rho, rac and cdc42 (particularly required for dendrite branching)
94
describe the mechanism by which dendrites branches
interstitial branching - formed along the dendrites 1. local activation of cdc42 lead to penetration of actin gel at dendrite surface 2. formation of transient filopodium 3. filopodium invaded by microtubules and stabilised as a new branch
95
name the purpose of dendrites that do not overlap each other when originating from the same cell body
ensures that neuron samples its receptive field evenly
96
name a molecules important in self-avoidance of dendrite branches in drosophila and vertebrates which structure of the dendrites plays part in this recognition of different CAMS?
drosophila - DSCAM vertebrates - protocadherins the growth cone

Mechanism Of Brain Development (2 decks)

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