Frizzled-PCP Pathway in D. melanogaster
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Frizzled-PCP Pathway in D. melanogaster
In multicellular organisms, epithelia form highly organized structures. Epithelial apical-basolateral polarity enables the tissues to perform functions such as vectorial transport of fluid or secretion of specialized components to either their apical or basal side. However, the function of some tissues requires an additional axis of polarity within an epithelium, namely uniform polarity of single cells or multicellular units within the plane of the epithelium, commonly referred to as epithelial PCP (Planar Cell Polarity). PCP has been found in the epithelium of organisms from flies to humans. In Drosophila, PCP signaling is required for the appropriate orientation of trichomes or hairs of the adult wing and for appropriate chirality of ommatidia in the eye, and may regulate asymmetric cell divisions of certain neuroblasts (Ref.1).

Planar organization of cells requires a conserved set of genes, known as the PCP genes. The PCP proteins Fz (Frizzled) and Dsh (Dishevelled) function as key players in PCP signaling. Although Fz and Dsh are also involved in Wg (Wingless)/WNT (Wingless-Type MMTV Integration Site Family) signaling, these proteins have independent functions in a non-canonical pathway dedicated to PCP. Other proteins involved in Drosophila PCP pathway in all tissues include Pk-Sple (Prickle-Spiny Legs), DRhoA, Strabismus (also called Van Gogh), RoK (Rho-Associated Kinase), JNK (Jun N-terminal Kinase), Zip (Zipper), MRLC (Myosin Regulatory Light Chain)/Sqh (Spaghetti Squash), and Flamingo/Stan (Starry Night). In addition, several genes have been identified that are required for polarity generation in specific tissues. For example, Fy (Fuzzy), In (Inturned) and MWH (Multiple Wing Hairs) only affect polarity in the wing, whereas mutations in Nmo (Nemo) and Roulette/Argos appear only to affect ommatidial polarity. The genes affecting polarity in all tissues are components of a common signaling pathway, responsible for reading and relaying a common polarity signal, whereas genes such as Fuzzy or Nemo act as tissue-specific effectors of this signaling pathway (Ref.2).

PCP signaling in Drosophila is mediated by the receptor Fz and transduced by Dsh. WNT ligands are believed to activate Fz but the WNT Ligand activating the Drosophila Fz receptor has not been identified yet. Drosophila Dsh is a modular protein of unknown function that is well conserved in relation to its vertebrate homologs. Alignment of family members reveals three conserved domains. The first, a DIX (Dishevelled-Axin) domain, is similar to a domain in murine Axin. The second contains a PDZ (PSD95-Discs Large-ZO1) domain, which recognizes and binds short motifs at the Carboxyl termini of proteins but may bind other motifs as well. PDZ domains can also form dimers. The third domain, called DEP (Dishevelled-EGL10-Pleckstrin), is conserved among a set of proteins that have in common the ability to regulate various GTPases, including both heterotrimeric G-Proteins and Ras-like small GTPases. DEP and PDZ domains signal to PCP pathway. A mutation in the DEP domain impairs both membrane localization and the function of Dsh in PCP signaling, indicating that translocation is important for function. Fz but not Fz2 recruit Dsh selectively to the membrane, and this recruitment depends on the DEP domain but not the PDZ domain in Dsh (Ref.3).

Planar polarity pathway downstream of Fz and Dsh consists of the small GTPase Rho and Msn (Misshapen). The Drosophila Msn gene, a member of the Ste20 kinase family, which acts downstream of Fz and Dsh activate the JNKK (Jun-N-terminal Kinase Kinase), which further activates JNK (Jun-N-terminal Kinase). JNK then enters the nucleus where it is responsible for activation of dJun (Drosophila Jun Oncogene)/Jra and dFos (Drosophila Fos Oncogene) transcription factors. The Puc (Puckered) gene is a transcriptional target of JNK signaling in Drosophila, and encodes a dual specificity protein phosphatase that acts as a negative regulator of JNK itself in a feedback loop. The nuclear signaling leading to the transcriptional activation of Dl (Delta) is specific to eye PCP in Flies. Rho activated by Fz and Dsh activates RoKRoK mediate a branch of the PCP pathway involved in ommatidial rotation in the eye and in restricting Actin bundle formation to a single site in developing wing cells. The primary output of RoK signaling is regulating the phosphorylation of non-muscle MRLC/ Sqh, and hence the activity of Zipper (Ref.4). Rac1 and CDC42 (Cell Division Cycle-42) have been implicated in the process of wing hair formation.  Ds (Dachsous) and Ft (Fat), both members of the Cadherin Superfamily, also play important roles in PCP Signaling. Ds act as a cue for PCP in the Drosophila wing, orienting cell-cell interactions by inhibiting the activity of the Protocadherin Ft (Ref.5).

Several other genes involved in general planar polarity establishment have been identified that do not yet fit into the Fz pathway. The Stbm gene shows the same phenotypic features as Fz and Dsh.  Similarly, the common planar polarity gene Pk-Sple does not show informative genetic interactions. It is not yet clear whether these are required for planar polarity in general. The recent identification of the molecules involved in the generation of planar polarity in Drosophila has increased our understanding of the molecular mechanisms involved and shed some light on the similarities and differences of planar polarization in distinct tissues (Ref.6).