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Cell polarity Flashcards

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AP® Biology flashcards Biology 101 flashcards
1
Q

what is cell polarity?

A

cell polarity is the organisation of proteins inside, and at the surface of, cells such that regions of the cell have distinct protein compositions
- the cell can thereby have different capabilities, morphologies and functions

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2
Q

why is cell polarity necessary? why do we study cell polarity?

A
  • it is necessary for cells to generate a wide variety of forms to perfom a diverse array of functions
  • polarity studies identify extrinsic signals are interpreted by a cell to produce specific changes in cell shape and function
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3
Q

what do cell polarity studies reveal?

A

Analysis of diverse cell types reveals that cell surface landmarks adapt common pathways for cytoskeleton assembly and protein transport/membrane trafficking to generate cell polarity

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4
Q

how is cell polarity developed in eukaryotes?

A
  1. marking the site of the cell for differentiation
  2. that site must be decoded - the cell needs to know that growth has occured there
  3. establishment of the site is needed for proteins to organise the cell cytoskeleton and form key vesicles, membranes and proteins - organisation of the axis
  4. maintaining the site so that the polarity continues to exist
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5
Q

which organism was mainly used to study cell polarity?

A

Budding yeast (Saccharomyces cerevisiae):
- yeast is genetically tractable, and the entire genome sequence is known
- it has been used to understand fundamental aspects of cell processes such as cell cycle, secretion and cell polarity

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6
Q

why is budding yeast used to study cell polarity?

A

Budding yeast must generate cell polarity to grow and divide
- it undergoes morphological changes in response to internal and external signals
- genetic screens in yeast have been central to the elucidation of these polarity pathways

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7
Q

How do internal signals in yeast affect its morphology?

A

Internal signals trigger growth and division signals to undergo cytokinesis and bud formation

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8
Q

how do external signals in yeast affect its morphology?

A

external signals such as pheromones trigger mating, and nutritional signals to trigger cell elongation

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9
Q

how can budding events be analysed in yeast?

A

yeast cells bud and divide in precise spatial patterns:
- budding can be analysed by staining cells with calcofluor (fluorescent dye)
- calcofluor binds to chitin in the yeast cell walls
- this approach allows the birth scars which mark the sites of previous cell separations to be viewed as bright rings on the cell wall

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10
Q

what determines the position where new buds grow?

A

The position of the new bud, which will grow to form a new daughter cell depends on the cell type:
- For budding yeast this refers to whether the cell is haploid or diploid.

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11
Q

how are haploid cells generated by budding yeast?

A
  • Haploid a and alpha cells bud in an AXIAL pattern in which both mother and daughter cells are constrained to form buds immediately adjacent to the previous site of cell separation bud
  • Haploid cells would rather be diploid cells so this helps them undergo a mating event
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12
Q

how are diploid cells generated in budding yeast?

A
  • Diploid cells bud in a BIPOLAR manner in which mother and daughter cells bud at the poles of their ellipsoidal cells.
  • Bud from the ends of the cells so move cells away to explore a wider nutritional environment
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13
Q

how were the genes involved in budding determined?

A

Genetic screens were carried out to identify mutants that could not bud in the expected pattern

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14
Q

which genes were found to be required for the yeast axial budding pattern from the genetic screens?

A

For the axial pattern (normally for haploid), genes identified include BUD10, BUD3, BUD4 and the septins:
- Products from these genes are involved in marking the mother bud neck during one cycle as a site for budding in the next cycle.
- Mutations in these do not have defects in diploid cells.
- Haploid mutant cells now mostly bud with a bipolar pattern, not axial

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15
Q

which genes were found to be required for the yeast bipolar budding pattern from the genetic screens?

A

For the bipolar pattern (normally for diploid): BUD8, BUD9, RAX2 and components of the actin cytoskeleton are involved:
- Products from these genes mark the ends of diploid cells.
- Haploid mutants in these genes still use the axial pattern but the bipolar pattern is disrupted

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16
Q

which proteins are responsible for decoding the site of polarity?

A

Bud1, Bud2 and Bud5 function together to signal to the polarity-establishment machinery the position of the bud site
- they function together in a GTPase cycle

Bud1 is GTPase, bud2 and bud5 activate/inactivate this activity
- bud1 ensure the correct machinery is available to establish the site

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17
Q

how is the site of polarity established?

A

By the Rho-GTPase cycle:
- once the cell has determined its budding landmarks, the info is fed to the polarity establishment machinery to polarise the cell cytoskeleton
- in yeast, the most important Rho-GTPase family for polarity establishment is Cdc42

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18
Q

what is Cdc42?

A

Cdc42 is a small GTPase of the Rho family,
- It is regulated through cycles of activation and inactivation by its binding partners Cdc24 (a GEF) and several GAPs.

It is a temperature-sensitive mutant:
at 24C cells can polarise, form a bud, grow and divide
at 37C cells show isotropic growth all over the surface and cannot show an axis of polarity
- at high temps, Cdc42 cannot function

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19
Q

How does Cdc42 function to establish cell polarity?

A

Bud1 recruits cdc24 which activates cdc42:
1. Cdc24 is a GEF of cdc42, and cdc24 binds to the active form of Bud1 at sites marked for budding
2. Cdc24-bud1 then converts Cdc42-GDP to active cdc42-GTP to allow establishment of the polarity site
3. cdc42 recruits Bni1 which forms the actin cytoskeleton, Sec3 which is recruited for exocyst vesicle docking to trigger cell growth and kinases to pair growth of cell with nuclear division

the outcome: a polarised yeast daughter cell with machinery for inheritance of genetic material and for movement of cytoplasmic organelles and other material from mother cell

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20
Q

which yeast cells generate cell polarity to mate?

A

Haploid yeast cells polarise and redirect their growth axes to mate with a partner

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21
Q

how to haploid cells trigger mating?

A

the mating response is chemotropic as the haploid cells secrete mating pheromone peptides

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22
Q

what is the process of haploid cell polarity generation for mating?

A

MATa cells secrete a-factor, MAT-alpha cells secrete alpha-factor:
- MATa cells have a Ste2 receptor that recognises alpha-factor
-MAT-alpha cells have a Ste3 receptor that recognises a-factor
- when the receptors recognise their respective pheromones, growth is activated

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23
Q

what kind of receptors are the pheromone receptors? how do they function?

A

Ste2 and Ste3 pheromone receptors are GPCRs
- they interact with a heterotrimeric G-protein for downstream signalling

process:
1. pheromone binds to pheromone receptor (e.g. a-factor to Ste3 on MAT-alpha. and alpha-factor to Ste2 on MATa)
2. this activates the G-protein
3. Beta-gamma subunit recruits a MAP-kinase cascade leading to cell-cycle arrest
4. Far1 binds to Cdc42 to recruit polarity establishment machinery

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24
Q

what kind of growth does yeast undergo?

A

Asymmetric growth: the daughter cells have different properties to mother cells as they inherit mRNAs that give them differing characteristics

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25
Q

which proteins have been identified to be crucial for yeast asymmetric growth?

A

Genetic screens identified Myo2 and Myo4 for asymmetric inheritance of proteins and mRNA

has been discovered that cargo adaptor proteins can be degraded in daughter cells to prevent backward movement of organelles back into the mother

26
Q

how are yeast limited in understanding cell polarity?

A

they are unicellular so cannot be used to understand the mechanisms involving intercellular interactions, especially in the case of growth tissues and multicellular organisms

27
Q

give an example of yeast cell polarity in disease:

A

Candidiasis and Candidaemia (invasive candidiasis):
- the fungus Candida albicans is a benign commensal member of the mucosal flora, but can cause mucosal disease
- if it invades tissues, there is substantial morbidity
- in vulnerable patients, it causes life-threatening blood infections, frequently seen in AIDS patients (30-50% fatal) - fungus can travel in blood and penetrate tissues and organs

C. albicans has a high level of homology to budding yeast (S. cerevisiae)
- studies in budding yeast add to our knowledge in polarity development of C. albicans

28
Q

How does C. albicans cause invasive candidiasis?

A

It is able to grow in yeast and hyphal forms - dimorphism:
- it can switch between these forms which is central to its virulency
- hyphal formation is stimulated at 37C by serum/neutral pH
- hyphae are more adherent to mammalian cells and can penetrate tissues
- yeast cells taken up by macrophages can switch to filamentous hyphal growth and lyse the macrophage
- yeast cells are carried effectively in the bloodstream for systemic infection, and then the hyphal cells can invade tissues

29
Q

what is cell polarity critical for?

A
  1. Asymmetric cell division – including cell fate decisions
  2. Epithelial cells – to make an effective barrier
  3. Cell migration e.g. in development
30
Q

what are the two main routes to cell fate decision diversity?

A
  1. Intrinsic: polar mother cells divide and generate daughters that have inherited different components
    - caused by localised determinants and asymmetric division
  2. extrinsic: daughters could be equal at birth but then become different by exposure to different environmental signals
31
Q

what are the 3 crucial steps in assymetric cell division

A
  1. Establishment of an axis of polarity – this involves marking a site, signalling and establishing
  2. Organisation and alignment of mitotic spindle is positioned along the axis
  3. Cell fate determinants are often distributed differentially to daughter cells
32
Q

what are PAR proteins?

A

PAR proteins form the core of a cell polarity network
- the output of the network is one of mutual antagonism
- the establishment of opposing and complementary membrane domains define the cell’s axis of polarity

they form 2 different fates which are mutually antagonistic, so oppose each other in interactions at the membrane
- forms a clear, defined axis of polarity

33
Q

what model organism was crucial in understanding asymmetric cell division by PAR proteins?

A

C. elegans (nematode)
- early development in C.elegans is essentially a well-defined series of asymmetric cell divisions.
- The first division of the zygote has been intensively studied.

34
Q

What is the process of asymmetric cell division occur in C. elegans

A
  • Polarisation starts with entry of sperm into the oocyte.
  • The position of entry defines the posterior end of the zygote.
  • The zygote - also called the P0 cell - then divides asymmetrically along the anterior-posterior axis.
  • This produces a larger anterior cell (AB) and a smaller posterior cell (P1).
  • The daughters are different in size and are committed to different cell fates
  • P1 gives rise to mesoderm/endoderm, AB gives rise to ectoderm
35
Q

which genes were discovered to cause asymmetric division in C. elegans?

A

A genetic screen to identify key players in this asymmetric division led to the discovery of the par genes (for partitioning defective mutants)
- 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.
- The PAR genes encode the PAR proteins par1-6 and the seventh member of the group is atypical protein kinase C (aPkc also known as PKC3 in C.elegans).
- Only Par2 is not conserved in other metazoans

36
Q

how is asymmetric division triggered?

A

Symmetry is broken on fertilization when the sperm delivers a microtubule organizing centre (MTOC). This site becomes the posterior pole and so defines the axis of polarity

37
Q

how is the axis of polarity established by PAR proteins?

A

Microtubules are filamentous structures which act as tracts to allow transport of proteins:
- The microtubules generated recruit Par 1 and Par2 and this antagonises anterior Par proteins and they accumulate at anterior cortical domain.

This results in distinct localizations of the par proteins.
- Par3/Par6/aPkc localise to the anterior cortex;
- Par1 and Par2 are at the posterior cortex
- Par5 maintains the boundary

38
Q

where are the different PAR proteins localised in an asymmetric cell?

A
  • Par3/Par6/aPkc localise to the anterior cortex;
  • Par 1 and Par2 are at the posterior cortex
  • Par5 maintains the boundary.
39
Q

how is the mitotic spindle in an asymmetric cell defined?

A

Phosphorylation is key in the feedback loops that allow the poles to be defined.
- Interactions between microtubules and the cortex results in pulling forces which act on the mitotic spindle which causes the spindle to be displaced TOWARD the posterior end
- LGL allows greater pulling force on the spindle to set up the asymmetric cell division plane

40
Q

how are PAR proteins distributed in asymmetric division?

A

Redistribution of the par proteins and cell fate determinants requires a directional and actin-myosin based process:
- Actin-myosin carries cell fate determinants to apical face
- Forms asymmetric division plane

41
Q

which model organism was crucial in understanding neuroblast cell division?

A

Drosophila
- drosophila have CNS progenitor cells called neuroblasts which are found in the ventral ectoderm

42
Q

what is the process of the Drosophila neuroblast division?

A
  1. neuroblasts delaminate and extrude from the neuroectoderm and begin to undergo asymmetric division
  2. each division forms a large apical daughter cell on top and a small basal cell beneath called a ganglion mother cell (GMC)
  3. the GMC divides only once more to form a neuron and a glial cell
  4. the apical daughter cell continues to divide in 4 more rounds to form more GMCs
43
Q

how is polarity established in the neuroectoderm?

A

Polarity is established when the cell stalk region is still in the neuroectoderm layer:
1. when neuroblasts delaminate, Cdc42, Par3 (Bazooka – in Drosophila)/Par6 are found in a stalk that continues to extend into the epithelium
2. After delamination, they continue to localise to the apical region and so in fully delaminated neuroblasts polarity is independent of surrounding cells
3. Baz anchors another complex (Insc/Pins) at the membrane in order to orient the mitotic spindle.
4. Scribble complex helps in spindle alignment

44
Q

why does the ganglion mother cell have a different cell fate to the apical daughter cell?

A

Cell fate determinants are transported in a basal direction to the Ganglion mother cell:
- This includes factors such as Prospero and Staufen which regulate expression of specific genes in the GMC.

Following cell division the GMC has a different fate because of asymmetric inheritance of these determinants

45
Q

how does most cell locomotion occur?

A
  • in animals, with the exception of sperm, almost all cell locomotion occurs by crawling on a solid substrate.
  • Cell movement is seen during development when individual cells or organisations of cells can move.
  • In adults, macrophages and neutrophils crawl to sites infection and fibroblasts move to repair injured tissue
  • Branched actin filaments beneath the cortex enable this to occur
46
Q

what 3 main activity is required for cell migration/movement?

A
  1. Protrusion – the pushing out of the plasma membrane in front of the cell
    - Lamellipodium often does protrusion
  2. Attachment – the actin cytoskeleton inside the cell is attached via interacting proteins across the plasma membrane to the substratum (e.g. extracellular matrix)
    - Protein will tether to ECM e.g. integrins which bind to actin inside the cell and ECM proteins via focal adhesions
  3. Traction – the bulk of the cell body is drawn forward through a process of contraction
47
Q

which actin structures are crucial in cell protrusion?

A

Filopodia, lamellipodia and stress fibres - these are filled with actin filaments

48
Q

what are filopodia?

A

microspikes which contain a dense core of bundled actin filaments

49
Q

what are lamellipodia?

A

sheet-like broad structures containing short, branched, cross-linked actin

50
Q

what are stress fibres?

A

bundles of actin filaments that are involved in the contractility needed to move the body of the cell forward
- they also disassemble the focal adhesions left behind

51
Q

which small Rho-GTPases are important in cell polarity establishment for cell migration?

A

Cdc42
Rac
Rho

signals triggering cell migration converge onto Rho small GTPases

52
Q

how do GTPase cycles work?

A

The proteins switch from active GTP-bound form and inactive GDP-bound form
- GEF (guanosine exchange factors) activate the proteins by converting GDP to GTP
- GAF (GTPase activating factors) inactivate the proteins by hydrolysing GTP to GDP

53
Q

what do the different GTPases generate in cell migration?

A
  1. cdc42 recruits filopodia microspikes
  2. Rac recruits lamellipodia
  3. Rho recruits stress fibres
54
Q

what is chemotaxis?

A

the movement of cells towards or away from a signal such as a diffusible chemical

e.g. movement of a neutrophil towards a site of bacterial infection

55
Q

how does neutrophil chemotaxis occur?

A
  1. Receptors on the surface of the neutrophils detect very low levels of bacterial chemoattractants peptides.
  2. The peptides can bind to G-protein coupled receptors and this triggers intracellular activation of a heterotrimeric G-protein.
  3. In turn this leads to activation of the Rac-GTPase leading to lamellipodial protrusion in the direction of the peptide gradient.
  4. Another pathway is switched on to activate Rho which enhances actin-myosin stress fibre-based contractility facilitating movement of the cell body.
56
Q

what is an epithelium?

A

The epithelium is the first tissue that emerges during development of the fertilized egg.
The epithelium has key roles in embryo morphogenesis and organ development.

57
Q

what are the key properties of an epithelium?

A
  • The apical side faces the external environment or lumen of the tissue; the basal side faces the basement membrane.
  • Lateral sides of epithelial cells adhere to each other through homophilic adhesion molecules, such as E-cadherin (bind to each other) - Not the strongest interactions but important in setting up polarity
  • 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 (like neuroectoderm)
  • Epithelial cells can rapidly lose the epithelial phenotype (epithelial mesenchymal transition – EMT) and re-acquire it (Mesenchymal epithelial transition – MET) (basis for cancers)
58
Q

how is epithelium established and maintained in Drosophila embryo cellularisation?

A
  • After zygote formation, there is a large number of nuclear divisions.
  • Nuclei line up around the membrane to form a syncytial ectoderm.
  • Cellularisation occurs where membrane forms around each nuclei, forming a complete epithelium (cellular mesoderm)
  • Actin and rho are involved in this
59
Q

how are junctions established and maintained in epithelia?

A
  • Centrioles are deposited to form microtubules to help traffic proteins such as Bazooka towards that end, and then can begin forming intracellular interactions.
  • Bazooka/PAR3 binds to E-cadherin which binds to the E-cadherin of another cell (adherens junctions) to form epithelium with apical face and basolateral face
  • Antagonism between the 2 faces is maintained by negative feedback
  • Actin cytoskeleton helps traffic proteins to the right place
60
Q

what complexes are involved in epithelial cell polarity?

A
  • PAR complex/Cdc42 - form apical face
  • Crumbs (CRB complex): CRB, Stardust (PALS in vertebrates) and PATJ (PALS1-associated tight junction homologue) - links apical membrane to actin cytoskeleton
  • Scribbled (SCRIB complex): Disks large homologue (DLG), lethal giant larva (LGL) and SCRIB) - forms basolateral face
61
Q

what is E-cadherin?

A

Transmembrane adherens junction proteins
- they join to each other via homophilic interactions

62
Q

what is epithelial-mesenchymal transition (EMT)?

A
  • EMT is a critical process during development and is also associated with cancer metastasis
  • It involves conversion of the epithelial apical-basal polarity axis into a migration axis with front-rear polarity.
  • 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)

Molecular cellular biology (13 decks)

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