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Cell and molecular extras > Lecture 23 Cell polarity 1 > Flashcards

Lecture 23 Cell polarity 1 Flashcards

1
Q

Define cell polarity

A

the organization of proteins inside, and at the surface of cells, such that regions of the cell have distinct protein compositions so the cell can have different capabilities, morphologies and functions

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2
Q

What is cell polarity required for

A

Asymmetric cell division

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3
Q

What is the main hypothesis surrounding cell polarity

A

A cell can generate daughters that are intrinsically different from one another.
Formulated more than a hundred years ago.

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4
Q

What did Whitman 1878 study, and what did he find

A

Leeches
Distinct cytoplasmic domains are differentially partitioned to descendants and that these differences were reflected in different cell lineages

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5
Q

What did Conklin in 1905 identify

A

5 different cytoplasmic types that were differentially inherited to determine tissue types

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6
Q

What are the key functional requirements to be able to polarize cells? x5

A
  1. Internal or external cues (signals)
  2. These signals need to mark the site
  3. The site needs to be decoded
  4. The site needs to be established i.e. machinery needs to respond to the signal
  5. The site needs to be maintained (may be temporary or permanent)
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7
Q

What did analysis of various cell types reveal about how cell polarity is generated?

A

Cell surface landmarks adapt similar pathways for cytoskeleton assembly and protein transport/membrane trafficking to generate cell polarity

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8
Q

What 3 processes is cell polarity involved in?

A

Asymmetric cell division (cell fate decisions)
Epithelial cells
Cell migration
i.e. necessary for a wide variety of forms to perform a diverse array of functions

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9
Q

Describe the polarity in an epithelial cell

A
  • Apical surface – contacts the environment
  • Lateral surface – seals paracellular space
  • Basal surface – anchored to ECM
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10
Q

Describe the polarity in a migrating cell

A

Extend dynamic lamellipodia and filopodia to drive forward protrusion

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11
Q

How were protein complexes in yeast, drosophila and c.elegans first identified?

A

Genetic screens

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12
Q

What acts as a scaffold? Build what? For?

A

• These polarity complexes build signalling centres that act as scaffolds for small Rho GTPases on specific membranes. This in turn controls shape by regulating acto-myosin cytoskeleton and directing protein/vesicular trafficking.

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13
Q

How are the protein complexes deployed?

A

• These complexes can be deployed in different combinations to yield distinct polarity outcomes

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14
Q

When is Rho active/inactive?

A 
Rho-GTP = active 
Rho-GDP = inactive
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15
Q

What activates a small GTPase e.g. Rho

A

GEF (GDP-GTP Nucleotide exchange factor)

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16
Q

What inactivates a small GTPase

A

GAP (GTPase activating protein)

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17
Q

Why must budding yeast generate cell polarity?

A

To grow and divide

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18
Q

Why is budding yeast relatively simple

A

It only defines one site for growth

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19
Q

What marks the site in yeast budding

A

Cortical membrane protein

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20
Q

What follows after marking the site in yeast budding

A

Decoding the site via a signalling complex

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21
Q

How is the site in yeast budding established?

A

Rho-GTPase Cdc42 is activated. It organises the cytoskeleton and drives trafficking pathways

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22
Q

How is the site in yeast budding maintained?

A

Feedback loops

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23
Q

Describe all the steps in yeast budding

A
  1. Marks the site using cortical membrane protein
  2. Decode the site via a signaling complex
  3. Establish the site – Rho-GTPase Cdc42 activated. It organises the cytoskeleton and drives trafficking pathways to form a bud and so form a daughter cell
  4. Maintaining the site using feedback loops which allow the site to continue to be recongised by stopping the signal becoming too dispersed
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24
Q

What is central to yeast polarity establishment step?

What would occur if this was deleted?

A

small Rho GTPAse Cdc42

Deletion of this will mean there is no budding/daughter cell formation and eventually death

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25
Q

What protein forms the core of a cell polarity network in many animal cells and in many developmental contexts

A

PAR proteins

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26
Q

What is the output of a cell polarity network and what do these define?

A

Opposing and complementary membrane domains that define a cell’s axis of polarity

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27
Q

Where were Par proteins first discovered

A

C.elegans

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28
Q

How does cell polarity occur in C.elegans in early development

A

Through a series of asymmetric cell divisions

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29
Q

What does polarisation begin with in C.elegans

A

entry of sperm into the oocyte

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30
Q

What does the position of sperm entry define in c.elegans

A

Defines the posterior end of the zygote

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31
Q

What is the c.elegans zygote also called? How does this form its daughter cells?

A

The zygote - also called the P0 cell - then divides asymmetrically along the anterior-posterior axis to produce a larger anterior cell (AB) and a smaller posterior cell (P1). The daughters are different in size and are committed to different cell fates.

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32
Q

AB cell produces

A

ectoderm

33
Q

P1 cell produces

A

Meso/endoderm

Germline

34
Q

Genetic screens identified what to be key player c.elegans polarisation?

A 
par genes 
(means partitioning defective)
35
Q

How were par mutants different to WT

A

Cells which did not divide asymmetrically, but down the middle
In par mutants the size and fate difference between the daughter cells AB and P1 are less pronounced and in extreme cases the two are identical.

36
Q

How many proteins do the Par genes encode

A

seven
Par 1-6
Par7

37
Q

How is Par 7 different

A

Atypical protein kinase C (aPKC, also known as PKC3 in C.elegans)

38
Q

Which Par is not conserved in other metazoans?

A

Par2

39
Q

When is symmetry broken on fertilisation?

A

When sperm delivers a MTOC = microtubule organising centre

40
Q

What does the MTOC become and define

A

This site becomes the posterior pole and so defines the axis of polarity.

41
Q

What do the MT generated upon sperm entry recruit? Why?

A

Par 1/2
They antagonise the anterior Par proteins so they accumulate at the anterior cortical domain
Par1/Par2 is a kinase, resulting in phosphorylation that is associated with proteins being unable to bind to the membrane

42
Q

Which proteins localise to the A vs P

A

A cortex = Par3/Par6/aPkc

P cortex = Par 1/2

43
Q

Which protein maintains the boundary

A 
Par 5 (14-3-3 protein which binds phosphorylated proteins) 
Also Par 4 kinase
44
Q

What associates with the Par complex at the A site

A

Cdc42

45
Q

What do interactions between the MT and cortex result in?

A

Pulling forces which act on the spindle to cause the spindle to be displaced towards the P end

46
Q

What strenghtens the pulling force towards the P end of the spindle?

A

LGL = lethal giant larva

47
Q

What does redistribution of par proteins and cell fate determinants require? Why?

A

A directional and actin-myosin based process

This is an active process so that cell fate determinants are trafficked to the A and so are inherited differently allowing for different cell lineages.

48
Q

What is specific cell type is found in drosophila CNS

A

Progenitor cells called neuroblasts are found within a specific region of a epithelial monolayer called the ventral neuroectoderm.

49
Q

How is polarity generated in drosophila CNS?

A

• These neuroblasts delaminate and undergo repeated rounds of asymmetric cell division.

50
Q

what does each division of a neuroblast give rise to?

A

GMC (small basal daughter cell)

Larger apical daughter

51
Q

What does the GMC give rise to?

A

Neuron

Glia cell

52
Q

How many times do GMC and apical cell divide

A

GMC - once

Apical - continues to divide asymmetrically

53
Q

When is polarity established in drosophila neuroblasts?

A

When cell is in neuroectoderm layer
PAr3/Par6 found in the stalk continue to extend the epithelium
After delamination, they continue to localise to the apical region

54
Q

Par3 in mammalians/c.elegans is called

A

Bazooka

55
Q

What does Bazooka do

A

anchors another complex (Insc/Pins) at the membrane in order to orient the mitotic spindle

56
Q

What does scribble do

A

Spindle alignment

57
Q

What is the first tissue to emerge during development of the fertilised egg

A

Epithelium

58
Q

What does epithelium have key roles in

A

Morphogenesis

Organ development

59
Q

Name 3 key properties of epithelial cells

A
  • Epithelial cells have polarised actin cytoskeleton – allows apical surface to constrict (important for gastrulation and tubulation)
  • Epithelial cells can orient their mitotic spindle to allow division in the plane of the epithelial sheet to increase their number or perpendicular to the sheet to generate different daughter cells.
  • Epithelial cells can rapidly lose the epithelial phenotype (epithelial mesenchymal transition – EMT) and re-acquire it (Mesenchymal epithelial transition – MET) which underpins cancer metastases
60
Q

What did in vitro studies on epithelial cells use

A

cells such as MDCK (Madin Darby canine kidney) cells to investigate mechanisms of these processes. These are epithelial cell lines.

61
Q

What are important in vivo models of epithelial cells

A

C.elegans and D.melanogaster

62
Q

What is set up during Drosophila embryo cellularisation?

A

De novo apicobasal polarity

63
Q

Define de novo

A

This means it hasn’t been done before and it has to be set up from nothing

64
Q

What occurs after fertilisation of the drosophila embryo in terms of the number of divisions, number of nuclei produced…

A

Following fertilization the early drosophila embryo undergoes 13 rounds of nuclear division (without cell division) to produce a syncytium of ~6000 nuclei underlying the outer membrane.

65
Q

What also occurs during cellularisation of drosophila embryo

A

In cellularization the plasma membrane simultaneously encapsulates all nuclei thus forming the embryonic epithelium. The polarity is set up as this ingression of the membrane around the nuclei happens.

66
Q

What did genetic screens on drosophila show about cellularisation

A

• As cellularization progresses specialized junctions form on lateral membranes just below the apical surface

67
Q

What do the junctions co-ordinate

A

The formation of a band of actin which essentially connects cells across the entire layer

68
Q

What are the junctions in invertebrates

A

Septate junctions form directly below these adherens junctions and prohibit movement of ions and small molecules.

69
Q

What are the junctions in vertebrates

A

Vertebrate epithelia also form adherens junctions but instead of septate junctions they form tight junctions and desmosomes

70
Q

what are the two complexes involved in establishing and maintaining junctions?

A

1) Crumbs complex (apical)

2) Scribbled complex (basal)

71
Q

Maintenance of cell polarity involves…

A

positive and negative feedback loops often involving phosphorylation

72
Q

Describe Crumbs (CRB) complex

A
  • CRB, Stardust (PALS in vertebrates) and PATJ (PALS1 associated tight junction homologue)
    APICAL
73
Q

Describe Scribbled (SCRIB) complex

A
  • Disks large homologue (DLG), lethal giant larva (LGL) and SCRIB
    BASAL
74
Q

What is the critical protein in drosophila that marks the site?

A

Transmembrane junctional proteins: E-cadherin

75
Q

What does E-Cadherin do? Ablation vs dispersion of this?

A

Critical junctional protein that marks the site. It binds to other E-cadherin and sets up an established polarity.

Ablating this, means you cannot set up the distinct cells so you cannot set up the polarity complexes.

Dispersing cells containing E-Cadherin means they can still come back together to reform epithelial cells

76
Q

What is EMT associated with?

A

Cancer metastasis

77
Q

What does EMT involve

A

It involves conversion of the epithelial apical-basal polarity axis into a migration axis with front-rear polarity.

78
Q

What is EMT triggered by

A

EMT is triggered by signals that lead to a loss of E-cadherin. There is also asymmetric activation of small Rho GTPases (Cdc42 and Rac1 at the front and RhoA at the rear)

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