Planar cell polarity

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Cartoon representation of Planar Cell Polarity in fly wing hair cells and mouse paw hair cellsFigure 1. (A and B) Drosophila cuticular wing hair cells of the adult wing. Wing hairs point distally (to the right) in wild-type (WT) animals (A) but lose orientation in PCP mutants (fz) (B). (C and D) Hairs on the mouse paw point away from the body (pointing up) in WT (C) but grow in a swirling pattern in PCP mutants (fz6) (D). Inspired by the work of Paul Adler (A and B) and Guo et al. (2004) (C and D). Cartoon representation of Planar polarity in fly and mouse epithelia.png
Cartoon representation of Planar Cell Polarity in fly wing hair cells and mouse paw hair cellsFigure 1. (A and B) Drosophila cuticular wing hair cells of the adult wing. Wing hairs point distally (to the right) in wild-type (WT) animals (A) but lose orientation in PCP mutants (fz) (B). (C and D) Hairs on the mouse paw point away from the body (pointing up) in WT (C) but grow in a swirling pattern in PCP mutants (fz6) (D). Inspired by the work of Paul Adler (A and B) and Guo et al. (2004) (C and D).

Planar cell polarity (PCP) is the protein-mediated signaling that coordinates the orientation of cells in a layer of epithelial tissue. In vertebrates, examples of mature PCP oriented tissue are the stereo-cilia bundles in the inner ear, [1] motile cilia of the epithelium, [2] and cell motility in epidermal wound healing. [3] Additionally, PCP is known to be crucial to major developmental time points including coordinating convergent extension during gastrulation and coordinating cell behavior for neural tube closure. [4] Cells orient themselves and their neighbors by establishing asymmetric expression of PCP components on opposing cell members within cells to establish and maintain the directionality of the cells. Some of these PCP components are transmembrane proteins which can proliferate the orientation signal to the surrounding cells. [5]

Contents

Research history

Planar cell polarity was first described in insects and then further defined in fruit flies ( Drosophila melanogaster ). Some of the earlier work on gene controlled polarity of fly wings was published by D. Gubb and A. García-Bellido in 1982 describing how the mutation of some genes resulted in a morphology change in the cuticle orientation on the fly body. [6]  The history of the PCP pathway as it was expanded by fly genetics work, which lead to the interesting names for PCP components like Frizzled , Van-gogh, and Dishevelled . These are typical nomenclature for new genes discovered in flies, which are often based on the description of the visual presentation of the mutant flies for each gene. Early PCP research focused on its role in embryology and genetics, but the discovery that PCP proteins were localized asymmetrically within the cell pushed the topic into the world of cell biology. [5]

There was a surge in interest in the Planar Cell Polarity pathway after conserved PCP genes were found to be involved in important vertebrate processes vertebrate gastrulation, mammalian ear patterning and hearing, and neural tube closure. [5] Discoveries from this popular wave of PCP research has found its involvement in polarized ciliary beating in the trachea and brain ventricles, [7] [8] oriented cell divisions, [9] lung branching, [10] and hair follicle alignment. [11] [12]

A major challenge to studying PCP is that the in vivo protein and cell contact signaling required to facilitate it are difficult to recapitulate in a cell culture dish. However, the recent advances in imaging technology and the expansion of genetic tools are helping to uncover how PCP works in the living cell and the role it plays in cell development and biology. [5]

Core planal cell polarity

Figure 2: Cartoon representation of Cuticular wing hair defect in Frizzled mutant flies.(A) The structure of Drosophila fly wing with and arrow showing the proximal and distal tips, (B) WT cuticular hairs in normal orientation towards the distal tip of the wing, (C) the disoriented cuticular hairs of the Frizzled(fz) mutant. The structures of the hairs are the same, only the orientation is different. Inspired by the work of David I. Strutt (2001) Cuticular wing hair defect in Frizzled mutant flies.png
Figure 2: Cartoon representation of Cuticular wing hair defect in Frizzled mutant flies.(A) The structure of Drosophila fly wing with and arrow showing the proximal and distal tips, (B) WT cuticular hairs in normal orientation towards the distal tip of the wing, (C) the disoriented cuticular hairs of the Frizzled(fz) mutant. The structures of the hairs are the same, only the orientation is different. Inspired by the work of David I. Strutt (2001)

Core planar cell polarity genes all characterized in Drosophila mutants affect many structures in Drosophila with PCP features including the hair and bristles across the fly body. The core PCP genes in Drosophila and other vertebrates are Frizzled (Fz), Flamingo (Fmi), Strabismus (Stbm)/Van-gogh (Vang), Prickle (Pk), Dishevelled (Dsh), Diego (Dgo), and trimeric G protein Gαo. [13]

Frizzled (Fz) -The first frizzled mutant in Drosophila was identified in 1982 by D. Gubb and A. Garcia-Bellido. The mutant had polarity defects in the wing, notum, haltere, legs, abdominal tergites and abdominal sternites. [6] Specifically, D. Gubb and A. Garcia-Bellido saw a polarity defect in the cuticular hairs and bristles on the wings. Later research found that the function of the Frizzled (Fz) gene in Drosophila melanogaster is required to coordinate the cytoskeletons of epidermal cells to orient cuticular hairs and bristles on the surface of the insect. “In Fz mutants it is not the structure of individual hairs and bristles that is altered, but their orientation with respect to their neighbors and the organism as a whole.” [14] As shown in Figure 2, in wild-type wing all hairs point towards the distal tip, but in Fz mutants the hairs point in a disordered manner. [14] Frizzled encodes a seven-pass transmembrane protein and because of this it gives epithelial cells the ability to transmit and interpret polarity information from neighboring epithelial cells. [14]

Flamingo (Fmi) – Another seven-pass transmembrane receptor, Flamingo is also a cadherin that localizes at cell-cell boundaries in the epithelia cells of Drosophila wing. In the absence of Fmi, planar polarity was distorted. Fmi localization at the proximal/distal cell boundary is first dependent on the localization of Frizzled at the same boundaries. [15]

Canonical and non-canonical Wnt pathways and PCP

The PCP signaling pathway includes several components (Fz, Dsh and Gαo) of the ‘‘canonical’’ Wnt signaling pathway. However the core PCP proteins can function independent of β-catenin to result in downstream changes to cellular cytoskeleton and are known as a ‘‘noncanonical’’ Wnt pathway. [13]

Cross protein interactions to establishing PCP asymmetry

The hallmark of the PCP system is the asymmetric and polarized membrane expression of PCP proteins. Dishevelled and Diego are cytoplasmic proteins and are recruited to the membrane by each other and by their association to the transmembrane PCP protein Frizzledl. [13] Strabismus/Vang is a four-transmembrane protein and can recruit cytoplasmic PCP protein Prickle. [13] It is known that Prickle can interact with Disheveled and perturb its recruitment by Frizzled. Through a feedback loop of the extracellular domains of Frizzled and Strabismus at the junctions of two neighboring cell membranes, the complex of Strabismus and Prickle and the complex of Frizzled and Disheveled and Diego are localized to opposite sides of the cells along the polarization axis. [13] Flamingo is thought to localize to both sides and plays a role in homophilic adhesion, the adhesion of cells by the interaction of similar cadherin types. [13] Failure of these PCP proteins to segregate correctly within a cell boundary can lead to a disruption in PCP such as with the hair cells on fly wings and mouse skin. [13]

See also

Related Research Articles

<span class="mw-page-title-main">Paracrine signaling</span> Form of localized cell signaling

In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.

Frzb is a Wnt-binding protein especially important in embryonic development. It is a competitor for the cell-surface G-protein receptor Frizzled.

Flamingo is a member of the adhesion-GPCR family of proteins. Flamingo has sequence homology to cadherins and G protein-coupled receptors (GPCR). Flamingo was originally identified as a Drosophila protein involved in planar cell polarity. Mammals have three flamingo homologs, CELSR1, CELSR2, CELSR3. In mice, all three have distinct expression patterns in organs such as the kidney, skin, and lungs, as well as the brain.

Prickle is also known as REST/NRSF-interacting LIM domain protein, which is a putative nuclear translocation receptor. Prickle is part of the non-canonical Wnt signaling pathway that establishes planar cell polarity. A gain or loss of function of Prickle1 causes defects in the convergent extension movements of gastrulation. In epithelial cells, Prickle2 establishes and maintains cell apical/basal polarity. Prickle1 plays an important role in the development of the nervous system by regulating the movement of nerve cells.

Strabismus was originally identified as a Drosophila protein involved in planar cell polarity. Flies with mutated strabismus genes have altered development of ommatidia in their eyes. Vertebrates have two Strabismus-related proteins, VANGL1 and VANGL2.

<span class="mw-page-title-main">Frizzled</span> Family of G-protein coupled receptor proteins

Frizzled is a family of atypical G protein-coupled receptors that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol.

<span class="mw-page-title-main">CELSR3</span> Protein-coding gene in the species Homo sapiens

Cadherin EGF LAG seven-pass G-type receptor 3 is a protein that in humans is encoded by the CELSR3 gene.

<span class="mw-page-title-main">Frizzled-2</span> Protein found in humans

Frizzled-2(Fz-2) is a protein that in humans is encoded by the FZD2 gene.

<span class="mw-page-title-main">Frizzled-5</span> Protein-coding gene in the species Homo sapiens

Frizzled-5(Fz-5) is a protein that in humans is encoded by the FZD5 gene.

<span class="mw-page-title-main">Frizzled-3</span> Protein-coding gene in the species Homo sapiens

Frizzled-3(Fz-3) is a protein that in humans is encoded by the FZD3 gene.

<span class="mw-page-title-main">Frizzled-6</span> Protein-coding gene in the species Homo sapiens

Frizzled-6(Fz-6) is a protein that in humans is encoded by the FZD6 gene.

<span class="mw-page-title-main">Frizzled-7</span> Protein-coding gene in the species Homo sapiens

Frizzled-7(Fd-7) is a protein that in humans is encoded by the FZD7 gene.

<span class="mw-page-title-main">Frizzled-8</span> Protein-coding gene in the species Homo sapiens

Frizzled-8(Fz-8) is a protein that in humans is encoded by the FZD8 gene.

<span class="mw-page-title-main">Frizzled-4</span> Protein-coding gene in the species Homo sapiens

Frizzled-4(Fz-4) is a protein that in humans is encoded by the FZD4 gene. Fz-4 has also been designated as CD344.

<span class="mw-page-title-main">DVL1</span> Human protein and coding gene

Segment polarity protein dishevelled homolog DVL-1 is a protein that in humans is encoded by the DVL1 gene.

<span class="mw-page-title-main">DVL2</span> Human protein and coding gene

Segment polarity protein dishevelled homolog DVL-2 is a protein that in humans is encoded by the DVL2 gene.

<span class="mw-page-title-main">DVL3</span> Protein-coding gene in humans

Segment polarity protein dishevelled homolog DVL-3 is a protein that in humans is encoded by the DVL3 gene.

<span class="mw-page-title-main">Dishevelled</span> Family of proteins

Dishevelled (Dsh) is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors. It takes its name from its initial discovery in flies, where a mutation in the dishevelled gene was observed to cause improper orientation of body and wing hairs. There are vertebrate homologs in zebrafish, Xenopus (Xdsh), mice and humans. Dsh relays complex Wnt signals in tissues and cells, in normal and abnormal contexts. It is thought to interact with the SPATS1 protein when regulating the Wnt Signalling pathway.

<span class="mw-page-title-main">PRICKLE1</span> Protein-coding gene in the species Homo sapiens

Prickle planar cell polarity protein 1 is a protein that in humans is encoded by the PRICKLE1 gene.

References

  1. ↑ Kelly, Michael; Chen, Ping (2007). "Shaping the mammalian auditory sensory organ by the planar cell polarity pathway". The International Journal of Developmental Biology. 51 (6–7): 535–547. doi:10.1387/ijdb.072344mk. ISSN   0214-6282. PMC   4158833 . PMID   17891715.
  2. ↑ Park, Tae Joo; Mitchell, Brian J; Abitua, Philip B; Kintner, Chris; Wallingford, John B (2008-06-15). "Dishevelled controls apical docking and planar polarization of basal bodies in ciliated epithelial cells". Nature Genetics. 40 (7): 871–879. doi:10.1038/ng.104. ISSN   1061-4036. PMC   2771675 . PMID   18552847.
  3. ↑ Caddy, Jacinta; Wilanowski, Tomasz; Darido, Charbel; Dworkin, Sebastian; Ting, Stephen B.; Zhao, Quan; Rank, Gerhard; Auden, Alana; Srivastava, Seema; Papenfuss, Tony A.; Murdoch, Jennifer N.; Humbert, Patrick O.; Boulos, Nidal; Weber, Thomas; Zuo, Jian (July 2010). "Epidermal Wound Repair Is Regulated by the Planar Cell Polarity Signaling Pathway". Developmental Cell. 19 (1): 138–147. doi:10.1016/j.devcel.2010.06.008. ISSN   1534-5807. PMC   2965174 . PMID   20643356. S2CID   21479886.
  4. ↑ Walsh, Gregory S.; Grant, Paul K.; Morgan, John A.; Moens, Cecilia B. (2011-07-15). "Planar polarity pathway and Nance-Horan syndrome-like 1b have essential cell-autonomous functions in neuronal migration". Development. 138 (14): 3033–3042. doi:10.1242/dev.063842. ISSN   1477-9129. PMC   3119310 . PMID   21693519.
  5. 1 2 3 4 Devenport, Danelle (2014-10-27). "The cell biology of planar cell polarity". Journal of Cell Biology. 207 (2): 171–179. doi:10.1083/jcb.201408039. ISSN   1540-8140. PMC   4210441 . PMID   25349257. S2CID   15616318.
  6. 1 2 Gubb, D.; García-Bellido, A. (1982-04-01). "A genetic analysis of the determination of cuticular polarity during development in Drosophila melanogaster". Development. 68 (1): 37–57. doi:10.1242/dev.68.1.37. hdl: 10261/47647 . ISSN   1477-9129.
  7. ↑ Tissir, Fadel; Qu, Yibo; Montcouquiol, Mireille; Zhou, Libing; Komatsu, Kouji; Shi, Dongbo; Fujimori, Toshihiko; Labeau, Jason; Tyteca, Donatienne; Courtoy, Pierre; Poumay, Yves; Uemura, Tadashi; Goffinet, Andre M (2010-05-16). "Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus". Nature Neuroscience. 13 (6): 700–707. doi:10.1038/nn.2555. ISSN   1097-6256. PMID   20473291. S2CID   17936238.
  8. ↑ Vladar, Eszter K.; Bayly, Roy D.; Sangoram, Ashvin M.; Scott, Matthew P.; Axelrod, Jeffrey D. (December 2012). "Microtubules Enable the Planar Cell Polarity of Airway Cilia". Current Biology. 22 (23): 2203–2212. doi:10.1016/j.cub.2012.09.046. ISSN   0960-9822. PMC   3518597 . PMID   23122850.
  9. ↑ Gong, Ying; Mo, Chunhui; Fraser, Scott E. (2004-07-14). "Planar cell polarity signalling controls cell division orientation during zebrafish gastrulation". Nature. 430 (7000): 689–693. doi:10.1038/nature02796. ISSN   0028-0836. PMID   15254551. S2CID   4366292.
  10. ↑ Yates, Laura L.; Schnatwinkel, Carsten; Murdoch, Jennifer N.; Bogani, Debora; Formstone, Caroline J.; Townsend, Stuart; Greenfield, Andy; Niswander, Lee A.; Dean, Charlotte H. (2010-03-10). "The PCP genes Celsr1 and Vangl2 are required for normal lung branching morphogenesis". Human Molecular Genetics. 19 (11): 2251–2267. doi:10.1093/hmg/ddq104. ISSN   1460-2083. PMC   2865378 . PMID   20223754.
  11. ↑ Guo, Nini; Hawkins, Charles; Nathans, Jeremy (2004-05-28). "Frizzled6 controls hair patterning in mice". Proceedings of the National Academy of Sciences. 101 (25): 9277–9281. doi: 10.1073/pnas.0402802101 . ISSN   0027-8424. PMC   438967 . PMID   15169958.
  12. ↑ Devenport, Danelle; Fuchs, Elaine (2008-10-12). "Planar polarization in embryonic epidermis orchestrates global asymmetric morphogenesis of hair follicles". Nature Cell Biology. 10 (11): 1257–1268. doi:10.1038/ncb1784. ISSN   1465-7392. PMC   2607065 . PMID   18849982.
  13. 1 2 3 4 5 6 7 Jones, Chonnettia; Chen, Ping (2007). "Planar cell polarity signaling in vertebrates". BioEssays. 29 (2): 120–132. doi:10.1002/bies.20526. ISSN   0265-9247. PMC   4158832 . PMID   17226800.
  14. 1 2 3 Vinson, Charles R.; Conover, Sharon; Adler, Paul N. (March 1989). "A Drosophila tissue polarity locus encodes a protein containing seven potential transmembrane domains". Nature. 338 (6212): 263–264. doi:10.1038/338263a0. ISSN   0028-0836. PMID   2493583. S2CID   4316603.
  15. ↑ Usui, Tadao; Shima, Yasuyuki; Shimada, Yuko; Hirano, Shinji; Burgess, Robert W; Schwarz, Thomas L; Takeichi, Masatoshi; Uemura, Tadashi (September 1999). "Flamingo, a Seven-Pass Transmembrane Cadherin, Regulates Planar Cell Polarity under the Control of Frizzled". Cell. 98 (5): 585–595. doi: 10.1016/s0092-8674(00)80046-x . ISSN   0092-8674. PMID   10490098. S2CID   15636248.
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