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cancer > 15. cacner and developmental biology > Flashcards

15. cacner and developmental biology Flashcards

1
Q

how many neurons are in the adult brain?

A

80 billion

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2
Q

give three ways that neurons can differ from one another

A
  1. neurotransmitters
  2. morphology
  3. receptors
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3
Q

when a stem cells divides what can it become?

A

another stem cell

a daughter cells - with less potential

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4
Q

why is very important to have self-renewal and differentiation balanced?

A
  • too much self renewal and not enough differentiation - large tissue, hyperplasia, tumour formation
  • too much differentiation and not enough self-renewal - reduced nervous system, small head and impaired tissue maintenance
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5
Q

when do NSC originate in Drosophila development?

A

in the embryo

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6
Q

what happens 4 or 5 hours in Drosophila development?

A

there is delamination of NSC from epithelial layer around embryo
>NSC undergo asymmetric division

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7
Q

when NSC undergo asymmetric division - what do they become?

A

another stem cells and a GMC (ganglion mother cell)

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8
Q

what do GMC tend to do?

A

divide once more to produce either neurones or glia

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9
Q

what from the epithelial layer of cells is translated into the epithelial layer?

A

the polarity - proteins at the apical cortex and proteins a the basal cortex

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10
Q

why is there asymmetric division

A

due to the components inherited by cells and the size of the cell

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11
Q

which cells is smaller: the NSC or the GMC?

A

the GMC

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12
Q

out of the apical and basal factors, which influence self-renewal and which influence differentiation?

A

> apical factors are important in maintaining self-renewal

>basal factors influence differentiation

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13
Q

what is asymmetrically segregated into GMC?

A

prospero - transcription factor that is held in the basal cortex of neural stem cells

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14
Q

what NSC divides and GMC is produced, what happens?

A

prospero is released from cortex and enters the nucleus

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15
Q

what is prospero key in?

A

key factor in switching the NSC from a self-renewing state to a differentiation state

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16
Q

what does CHIP stand for and what does it identify?

A

chromatin immuno-precipitation

>find where TF bind in genome

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17
Q

how does CHIP work?

A

cross link DNA with TF and pull down with antibody

>use microarray/next gen seq to identify sequence

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18
Q

what technique can be used to map protein-DNA interaction in vivo? and give a benefit of this

A

DamID - DNA adenine methyltransferase Identification

>does not require antibodies

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19
Q

how does DamID work?

A

> protein of interest fused to E coli enzyme that methylates adenines at specific sites
express at low level
where protein binds will methylate adenine
v little methyl adenine in DNA to interfere with results
cut out methyl adenine using enzymes that cut these locations
amplify and determine sequence

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20
Q

what sort of genes does prospero bind? and how was this determined?

A

it binds and represses cell cycle genes and NSC genes and activates differentiation genes
>DamID and comparing expression level with prospero mutants

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21
Q

where does prospero binds?

A

strongly to the intergenic regions of cyclin E genes

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22
Q

In terms of cancer, what is prospero?

A

a tumour suppresser

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23
Q

what is seen in prospero mutants and what can this lead to?

A

continue to self-renew and do not differentiate - keep dividing with no queues to differentiate
>this can lead to tumours

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24
Q

why are MARCM (mosaic analysis with a repressible cell marker) models useful?

A

you can make clones of cells during development that are mutants and label them with GFP, if entire embryo was mutant then it would die as embryo

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25
Q

prospero MARCM showed tumour formation in mice brains, these cells are dividing but are they really cancerous?

A

take cells and put them into abdomen of other fly - these tumours undergo metastasis
>tumours can be serial transplanted for at least two years

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26
Q

describe the protocol used to determine what was working with prospero to repress NSC genes and promote differentiation genes

A

> extract sequence from prospero binding regions
filter non-exonic regions and conserved sequences
top hit = palindrome, that looks nothing like prospero binding sequence i.e. suggests another factor binds near prospero

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27
Q

once the sequence for the protein that binds near prospero and help mediate differentiation was identified, what was done next?

A

yeast one-hybrid screen
>several copies of motif placed upstream of reporter gene
>transform cDNA libraries into yeast (all protein in embryo fused to AD)
>yeast that have factor which binds motif express reporter

28
Q

what factor was determine to bind this conserved motif? and where is this expressed?

A

lola

>in the developing nervous system

29
Q

what type of protein is lola?

A

BTB zinc finger TF

30
Q

how many splicing isoforms are these of lola? and what do they all have

A

25

BTB dimerization domain

31
Q

where is lola expressed?

A

post mitotic neurones - this is turned on as soon as the neuron is born

32
Q

name the protein that is a marker for NSC and holds prospero at the cortex?

A

mira

33
Q

what type of cells is lola expressed in?

A

neurons, not glia

34
Q

what does lola bind?

A

lola binds and represses neural stem cell genes

>represses key NSC genes like deadpan

35
Q

how many genes overlap between prospero and lola?

A

259

36
Q

is lola a TS?

A

yes
>KO tumour cells formed expressed NSC markers and actively divided - normally undetectable levels of division in adult brain

37
Q

what happens in terms of differentiation with lola mutants?

A

cells get signal to differentiate, but without lola NSC are not kept off and cells revert to NSC - gradually express NSC markers
>this forms tumours in the brain

38
Q

what does the removal of lola result in?

A

de-differentiation in immature neurons

39
Q

how does a neurone become mature?

A

send out axons and form synapses with other cells

40
Q

what happens when lola is removed from mature neurones?

A

nothing

41
Q

how will understanding what maintains repression of NSC genes in mature neurones affect therapeutics?

A

> better understanding of how some brain tumours form
better understanding of certain resistance to therapies
better understanding = better therapy
if we can control de-differentiation we can instruct brain to repair damaged tissue

42
Q

how can we identify factors maintaining differentiation in mature neurones?

A

yeast 2 hybrid
>take lola bound to GAL4, this binds UAS of his3
>when bound to binding partner bound to AD there is expression of His3

43
Q

how many colonies were identified in Y2H?

A

111 with good confidence

44
Q

what sorts of things did the Y2H screen identify?

A

chromatin remodellers, TFs and lncRNA

45
Q

what % of the hits in Y2H were lncRNA?

A

60%

46
Q

what does lola recruit? and what is this key for?

A

NurD complex which moves around nucleosomes and recruits HDAC - promoting turn off of NSC genes
>this is what keeps neural stem cells repressed

47
Q

why is lola no longer required in mature neurones?

A

the DNA is in its repressed state and so cells wont de-differentiate

48
Q

name the lncRNA that is segregated into the GMC? and what does this express?

A

copa

>micropeptide of about 30 amino acids that interacts with lola and affects its function

49
Q

what happens when copa is KO?

A

this results in fewer GMC dividing (normally divide once more)

50
Q

what is the current hypothesis regarding copa?

A

> micropeptide binds and inhibits lola (cleave/degrade)
this prevents pre-mature differentiation
if lola acts prematurely then GMC stop dividing an will have one less neurone in brain

51
Q

in terms of cancer what type of protein is this micropeptide?

A

an oncogene

52
Q

describe the balance between symmetric and asymmetric division in the developing NS

A

NSC divide symmetrically amplifying the pool of NSC - occurs early in neurogenesis
>asymmetrically divides - maintain NSC whilst producing progeny.

53
Q

what two types of signalling promote symmetric NSC division?

A

Notch and Hippo

54
Q

what does activation of the hippo pathway lead to?

A

repression of transcription factor yorkie

55
Q

what does over activation of the hippo pathway cause?

A

over proliferation of NSC

>results in hyperplasia (this is often the initial stage of developing cancer)

56
Q

what happens when hippo is KO?

A

this reduces number of NSC

57
Q

what is associated with brain tumours in humans?

A

activation of hippo signalling - promotes symmetric division to drive tumour growth
>it may be amplified and over expressed

58
Q

describe notch signalling

A

delta ligand interacts with notch
>intracellular notch released into cell
>this enters nucleus and interacts with Rbpj
>this interactions promotes gene expression

59
Q

what genes does notch signalling activate?

A

genes associated with NSC proliferation in the NS

60
Q

what happens when notch signalling is inhibited?

A

neural stem cells asymmetrically divide into neuroblasts.

61
Q

what happens when notch signalling is increased in drosophila? and how might this increased signalling come about?

A

this results in brain tumours

>increased expression of intra cellular notch

62
Q

what happens when Rbpj is KO in mice brains?

A

there are fewer NSC symmetric divisions - Rbpj is required to drive normal proliferation

63
Q

what is increased notch signalling associated with in humans?

A

brain cancer

64
Q

in most human cases Notch promotes tumour growth, what does it do in other cases?

A

supresses tumour growth - context is important

65
Q

what sort of inhibitors have are in clinical trials in terms of notch signalling? and what is bad about this?

A

gamma secretase inhibitors - this means intracellular notch cannot be cleaved
>not v specific and so there are lots of off target effects

66
Q

why does inhibiting gamma secretase have lots of off target effects?

A

> notch is used in many other pathways

>this enzyme is not just used to cleave notch

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