Planar Cell Polarity pathway

Stable Identifier
Drosophila melanogaster
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To perform many of their functions, cell structures often require not only positional but also vectorial information. This form of polarisation is usually referred to as planar cell polarity (PCP) or tissue polarity. In Drosophila, PCP can easily be seen on several external adult structures such as the precisely aligned hairs on wing cells and in the arrangement of the building blocks, the ommatidia, of the compound eye.

In the wing blade, each cell grows a distally pointing, actin-rich hair close to its distal vertex. The hair orientation process relies solely on directional cytoskeletal rearrangements without an apparent requirement for a transcriptional response. A more complex polarisation is to be found in the eye. Within each ommatidium, the rhabdomeres of the six outer (R1 to R6) and two inner (R7 and R8) photoreceptors are organised into a trapezoid pattern that is invariant between ommatidia. In addition, the ommatidia are aligned with respect to the anterior-posterior and dorso-ventral axes. The cell fate specification of the R3 and R4 photoreceptors is key to the precise ommatidial polarity. PCP mediated competition between R3 and R4 results in expression of target gene Delta (DL) in the R3 cell. The ligand DL binds to its receptor Notch (N), thus activating the Notch signalling pathway, in the neighbouring R4 cell. The resulting R3 against R4 cell fate now determines the direction of rotation and positioning of the photoreceptors in the mature cluster.

In both Drosophila wing and eye the PCP mechanism can be basically generalised in the following way.

The core components of PCP signalling interact to establish polarity in the cell or set of cells. This results in polarised localisation and activation of associated cytoplasmic components. These direct the PCP 'signal' to a variety of downstream effectors. The core components include the membrane localised atypical cadherin Starry Night (STAN) aka Flamingo (Fmi), the seven-pass transmembrane protein Frizzled (FZ), the four-pass transmembrane protein Van Gogh (VANG) aka Strabismus (Stbm), along with with the prenylated LIM domain protein Prickle (PK) aka Spiny Legs, Dishevelled (DSH) and the ankyrin repeat protein Diego (DGO) which are present in the cytoplasm but associate with the membrane.

There is also a second group of PCP regulators including the atypical cadherins Dachsous (DS) and Fat (FT) along with the type II transmembrane protein Four-jointed (FJ). It appears that FJ is at its most active in the Golgi. FJ genetically interacts with DS and FT (FJ -> DS -> FT). It's proposed that it may promote or mediate post-translational modification of these atypical cadherins. However, the large size of DS and FT means analysis of potential post-translational modifications is difficult (Strutt et al., 2004).

In each cell, before the onset of PCP signalling, STAN, FZ, VANG, DS, and FT are uniformly distributed on the cell surface with PK, DSH, and DGO present in the cytoplasm. During PCP signalling, DS binds to FT in an adjacent cell (heterophillic protein-protein interaction) along with STAN binding to its neighbour in the adjacent cell (homophillic protein-protein interaction). Polarisation of the PCP components along the proximal-distal and R3-R4 cell boundaries now occurs as part of a bistable switch mechanism. FZ recruits DSH and DGO to the R3/Distal cell boundary while VANG recruits PK to the R4/Proximal cell boundary. It is believed that there is an interaction (mutual recruitment) between STAN:FZ:DSH:DGO complexes on one side and STAN:VANG:PK complexes on the adjacent cell surface. It is controversial to say whether communication is mediated via STAN homodimers, or through a direct contact between FZ and VANG. However, both these complexes antagonise each other, thus inhibiting formation of the oppositely orientated complex. This leads to asymmetric enrichment and distribution of the main PCP components. The FZ:DSH:DGO complex becomes enriched at the Distal/R3 cell boundary while the proteins that function as antagonists of FZ, the VANG:PK complex becomes enriched at the Proximal/R4 boundary. STAN becomes enriched on both sides, probably stabilising both complexes.

PK can also interact with DSH, causing a reduction of DSH membrane localisation. This can be seen as a negative feedback loop. However, DGO can compete with PK for DSH binding and so remove the inhibitory action of PK on PCP signalling. DGO stabilises the FZ:DSH complex and the signal now appears to branch with DSH interacting with both RHO1 and RAC1 small GTPases.

In the RHO1 branch, RHO1 binds to DSH via the Dishevelled Associated Activator of Morphogenesis bridging protein (DAAM) and becomes activated. Activated RHO1 (the GTP-bound form) binds Rho kinase (ROK) which becomes activated. Non-muscle Myosin II is a hexamer composed of two of each of the following: heavy chain Zipper (ZIP), regulatory light chain Spaghetti squash (SQH), and the essential light chain MLC-C. Myosin phosphatase is a heterotrimer composed of a protein phosphatase catalytic subunit Flapwing (FLW) or PP1-87B; a Myosin phosphatase targeting subunit, Myosin binding subunit (MBS) or MYPT-75D; and a small subunit of unknown function sometimes referred to as M20. Activated ROK phosphorylates SQH, this leads to a change in the conformation and increase in ATPase catalytic activity of ZIP. Multivalent bipolar filaments are more readily formed which are more capable of binding multiple actin filaments. However, Myosin phosphatase dephosphorylates SQH leading to the inactivation of non-muscle Myosin II. Myosin phosphatase is itself negatively regulated through phosphorylation of MBS by ROK. Thus, ROK doubly activates non-muscle Myosin II by direct phosphorylation of SQH and inactivation of Myosin phosphatase by phosphorylating MBS.

Additionally, in the wing, proximally localised VANG acts via the Planar Polarity Effector (PPE) proteins Inturned (IN), Fuzzy (FY), and Fritz (FRTZ) to stabilise the formin inhibitor protein, multiple wing hairs (MWH) resulting in the regulation of actin polymerisation and its inherent effect on hair formation.

In the RAC1 branch, after DSH binds to RAC1 there is genetic evidence to suggest that the JNK signalling cascade is activated by the STE20 kinase Misshapen (MSN). The MKK7 orthologue Hemipterous (HEP) is phosphorylated by components downstream of RAC1. Additionally, components from the RHO1 branch, FLW, MBS, and ZIP, appear to interact genetically with members of the JNK pathway, namely Basket (BSK), HEP, and Puckered (PUC). Nonmuscle myosin acts upstream, mediating an activating signal on JNK.

Literature References
PubMed ID Title Journal Year
17230199 Frizzled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility

Seifert, JR, Mlodzik, M

Nat Rev Genet 2007
14730010 Planar polarity from flies to vertebrates

Fanto, M, McNeill, H

J Cell Sci 2004
16212491 Planar cell polarization: an emerging model points in the right direction

Klein, TJ, Mlodzik, M

Annu Rev Cell Dev Biol 2005
14757640 Cleavage and secretion is not required for Four-jointed function in Drosophila patterning

Strutt, H, Mundy, J, Hofstra, K, Strutt, D

Development 2004
16299762 Long-range coordination of planar polarity in Drosophila

Strutt, H, Strutt, D

Bioessays 2005
17008934 Planar cell polarity signaling: a common mechanism for cellular polarization

Jenny, A, Mlodzik, M

Mt Sinai J Med 2006
17574020 Planar polarity and tissue morphogenesis

Zallen, JA

Cell 2007
12806028 Coupling planar cell polarity signaling to morphogenesis

Axelrod, JD, McNeill, H

ScientificWorldJournal 2002
17563758 Planar cell polarity: one or two pathways?

Lawrence, PA, Struhl, G, Casal, J

Nat Rev Genet 2007
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