Planar cell polarity Flashcards
Define Planar Cell Polarity (PCP).
Tissue polarity, or Planar Cell Polarity (PCP), is a property shown by some epithelia to become polarized within the plane of the epithelium, along an axis perpendicular to the apical-basal axis of the cell.
PCP can be found throughout the animal kingdom. The coordinate organization of scales in fish, feathers in birds and hair in mammals are easily visualized examples of PCP. However, PCP is also found in internal tissues, such as stereocilia in the inner ear, and this planar organization of stereocilia is essential for normal hearing and balance.
Give an example of the importantce of PCP in Drosophila and humans.
The simplest and best-understood form of PCP is the organization of hairs in the Drosophila wing. Each cell in the wing produces a single cellular extension called a trichome or hair. All hairs coherently align along the proximal-distal axis, pointing towards the distal end of the wing. PCP genes control both the orientation and the subcellular localization of the hair, as well as the number of hairs produced by each cell. Disruption of the PCP signal produces different classes of phenotype, which are used to classify PCP genes into different groups. Mutations in fz, dsh, fmi and several other PCP genes primarily affect the orientation of wing hairs but not their number. Mutations in the genes encoding novel proteins such as fuzzy (fy) and inturned (in), as well as in the uncharacterized mutant multiple wing hair (mwh), result in multiple hairs growing from a single cell.
This can be applied to the human body, e.g. inner ear hairs that are polarised. Polarised sensory hair cells in the inner ear each have a single, microtubule based structure; the kinocilium. The kinocilium is flanked by actin-rich microvillus-like stereocillia. These hair cells are aligned. Movement of stereocilia or kinocilium results in the release of neurotransmitter onto the vestibular branches of the vestibulocochler nerve. The cerebellum receives constant updated sensory information which it sends to the motor areas of the cerebral cortex. The motor cortex can then adjust its signals to maintain balance. When this process is disrupted it can cause deafness syndromes.
What is normal PCP required for in humans?
- Hair patterning
- Embryonic convergent extension movements
- Gastrulation
- Neural tube closure
- Inner ear patterning
- Axon guidance
- Cardiovascular development
- Angiogenesis
- Kidney development (polycystic kidneys)
Cells are polarised during development. Name a movement due to PCP signalling and a defect when it goes wrong.
During development cells are polarised, e.g. during gastrulation- this creates the conversion extension movement. This is important in neural tube closure, in which a conversion extension movement leads to the closure of the neural tube. Problems in this process can lead to spina bifida.
What is Planar Cell Polarity (PCP) signalling also known as?
Non-canonical Wnt signalling.
Name some diseases resulting from abnormal PCP.
- Deafness
- Polycystic kidney disease (PKD)
- Neural Tube Defects (NTDs), e.g. spina bifida
- Robinow syndrome (a severe skeletal dysplasia)
- Idiopathic scoliosis phenotypes
Fat Stan
What molecules are involved in PCP signalling?
-
Core Genes/Stan System
- Fmi, Fz, Dsh, Vang, Pk
-
Upstream Organisers/Fat/Ds system
- Fat/Ds/Fjj
-
PCP Effectors
- RhoA, Daam, Rok; Jnk; (In, Fz, Mwh)
How does Dishevelled mediate canonical and non-canonical Wnt signalling?
- Canonical: Wnt signals are revieved by Frizzled (Fz) receptor and a LRP co-receptor. The signal is transduced through Dishevelled and various other proteins, leading eventually to the stabilisation of beta-catenin, which then together with LEF/TCF controls the transcription of target genes.
- Non-canonical: also known as the PCP cascade. A signal is recieved by a Fz receptor, and transduced via Dishevelled to RAC and RHO, which then activate downstream targets to modulate the actin cytoskeleton.
Outline Frizzled in PCP.
Frizzled is a transmembrane protein that was identified in PCP mutants. Frizzled is redundant with Fz2 for it’s Wnt signaling function.
Outline Dishevelled in PCP.
Dsh is a multi-domain protein that works differently in the Wnt and PCP pathways. Gain of function analysis implies that the three domains of Dsh act differently in Wnt vs PCP signaling:
- Wnt: DIX and PDZ (DEP dispensable)
- PCP: PDZ and DEP (DIX dispensable)
A specific Lys→Met mutation in Dsh in the DEP domain leads to PCP rather than Wnt signaling.
What are the core PCP genes?
- Frizzled
- Dishevelled
- Vang-gogh (AKA Stbm): 4-pass transmembrane
- Prickle: LIM domains, farnesylation
- Flamingo (AKA Stan): 7-pass transmembrane, protocadherin domains
- Diego: Ankyrin repeat protein
How are tissue polarity molecules distributed in cells? Give examples of PCP molecules.
Many tissue polarity molecules are asymmetrically distributed in the cells in which PCP is established. This has been particularly well studied in the Drosophila wing.
Most PCP proteins are initially symmetrically distributed on the cell membranes. At 26-30 hours after pupation (APF), these proteins relocalize to specific membrane domains.
- The atypical cadherin Fmi (Flamingo) becomes transiently localized on both the proximal and distal sides, and depleted from the anterior and posterior cell membranes.
- The ankyrin repeat protein Diego is also thought to accumulate on both proximal and distal membranes.
- Fz and Dsh become localized only to the distal membrane.
- Stbm (Van-Gogh) and Pk (Prickled) localize solely on the proximal side.
What happens when PCP genes are mutated?
Although mutations in PCP genes result in loss of the coordinate, planar organization, cells maintain their normal apical-basal polarity and overall structure.
What are the interactions between PCP signalling molecules?
- Fz binds Dsh
- Vang binds Pk
- Fz CRD binds Vang
- Pk can bind Dsh and block it’s membrane localisation
What system is upstream of the Fz/Dsh pathway?
Fat/Dachsous system:
- Four-jointed (Fjj): a Golgi enzyme
- Fat (Ft): large, atypical cadherin
- Dachsous (Ds): large, atypical cadherin
- Fat and Ds form heterodimers
Describe the Ds/Fj gradient in the Drosophila wing.
In the wing, Ds and Fj genes play an important role in PCP. Ds and Fj are expressed in opposing gradients in the wing and in the eye. Unlike other core PCP proteins, Ds and Ft do not localize asymmetrically along the proximal-distal axis within wing cells. They are located where Fz, Dsh and Pk localize. Fj, Ft, Ds and Atro act upstream of Fz and the other tissue polarity genes.
Fj is expressed distally, and Ds proximally.
How is PCP established?
PCP is established through the localization of mutually exclusive subsets of core PCP proteins to opposing domains along the cell cortex, forming a pattern that propagates throughout the tissue. PCP protein patterns develop from an initially symmetric distribution that gradually resolves into two complementary domains, with Fz, Dsh and Dgo complexes typically accumulating on one side of each cell, and Vang and Pk enriched on the other; Fmi is present on both sides.
How are PCP molecules organised in wing hair polarity?
Cells of the D. melanogaster wing blade are asymmetrically patterned by proximal accumulations of Van Gogh (Vang) and Prickle (Pk) (both shown in purple) that are complementary to distal accumulations of Frizzled (Fz), Dishevelled (Dsh) and Diego (Dgo) (shown in green). These patterns govern the distal positioning and orientation of a single actin-based trichome in each cell of the wing epithelium.
How to PCP components affect physical cell linkages in Drosophila wings?
Asymmetric PCP signalling components form junctional signalling complexes that are physically linked from cell to cell. Both Fz and Vang are transmembrane proteins that associate with physically linked Flamingo (Fmi) homodimers established between the opposing membranes at cell–cell junctions. Distal accumulations of Fmi and Fz are asymmetrically clustered through the activity of Dsh and Dgo, whereas proximal Fmi and Vang complexes are enriched by the activity of Pk.
(Picture a nearby Prickly Van-Gogh with a Flamingo, and Dishevelled/Frizzled Diego in the distance…with a Flamingo)
How is polarity established in a single cell vs. a group of cells?
The asymmetric localization of a molecular cue can be sufficient to polarize the behaviour of a single cell; however, for groups of cells in an epithelium to collectively polarize, polarity information must be transmitted between neighbouring cells. Such cell–cell communication of planar polarity is primarily facilitated through the physical interactions of PCP signalling complexes at cellular junctions, of which the seven-pass (7 transmembrane domains) atypical cadherin Fmi is an essential component. Extracellular interactions of cadherin repeat domains promote the formation of Fmi homodimers across apical cell–cell junctions, which result in increasingly stable structures. These stable transmembrane accumulations link PCP signalling complexes in neighbouring cells, propagating a uniform, cooperative pattern of polarity information
What are some of the PCP molecules downstream of Dishevelled?
- RhoA: small G protein, binds Rho-associated kinase which activates Myosin regulatory light chain which directs cytoskeletal organisation. Mutants result in loss of PCP in flies.
- DRok: mutants result in multiple hairs per cell.
How is PCP linked to cancer?
- PCP is thought to be involved in metastasis, Epithelial-Mesenchymal Transition (EMT) and angiogenesis.
- Rho GTPases affect EMT and cell migration
