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1
Devenport, Danelle. "The cell biology of planar cell polarity." Journal of Cell Biology 207, no. 2 (October 27, 2014): 171–79. http://dx.doi.org/10.1083/jcb.201408039.
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Planar cell polarity (PCP) refers to the coordinated alignment of cell polarity across the tissue plane. Key to the establishment of PCP is asymmetric partitioning of cortical PCP components and intercellular communication to coordinate polarity between neighboring cells. Recent progress has been made toward understanding how protein transport, endocytosis, and intercellular interactions contribute to asymmetric PCP protein localization. Additionally, the functions of gradients and mechanical forces as global cues that bias PCP orientation are beginning to be elucidated. Together, these findings are shedding light on how global cues integrate with local cell interactions to organize cellular polarity at the tissue level.
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Axelrod, Jeffrey D., and Helen McNeill. "Coupling Planar Cell Polarity Signaling to Morphogenesis." Scientific World JOURNAL 2 (2002): 434–54. http://dx.doi.org/10.1100/tsw.2002.105.
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Epithelial cells and other groups of cells acquire a polarity orthogonal to their apical–basal axes, referred to as Planar Cell Polarity (PCP). The process by which these cells become polarized requires a signaling pathway using Frizzled as a receptor. Responding cells sense cues from their environment that provide directional information, and they translate this information into cellular asymmetry. Most of what is known about PCP derives from studies in the fruit fly,Drosophila. We review what is known about how cells translate an unknown signal into asymmetric cytoskeletal reorganization. We then discuss how the vertebrate processes of convergent extension and cochlear hair-cell development may relate toDrosophilaPCP signaling.
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Mlodzik, Marek. "Planar cell polarity: moving from single cells to tissue-scale biology." Development 147, no. 24 (December 15, 2020): dev186346. http://dx.doi.org/10.1242/dev.186346.
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ABSTRACTPlanar cell polarity (PCP) reflects cellular orientation within the plane of an epithelium. PCP is crucial during many biological patterning processes and for organ function. It is omnipresent, from convergent-extension mechanisms during early development through to terminal organogenesis, and it regulates many aspects of cell positioning and orientation during tissue morphogenesis, organ development and homeostasis. Suzanne Eaton used the power of Drosophila as a model system to study PCP, but her vision of, and impact on, PCP studies in flies translates to all animal models. As I highlight here, Suzanne's incorporation of quantitative biophysical studies of whole tissues, integrated with the detailed cell biology of PCP phenomena, completely changed how the field studies this intriguing feature. Moreover, Suzanne's impact on ongoing and future PCP studies is fundamental, long-lasting and transformative.
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Tower-Gilchrist, Cristy, Stephanie A. Zlatic, Dehong Yu, Qing Chang, Hao Wu, Xi Lin, Victor Faundez, and Ping Chen. "Adaptor protein-3 complex is required for Vangl2 trafficking and planar cell polarity of the inner ear." Molecular Biology of the Cell 30, no. 18 (August 15, 2019): 2422–34. http://dx.doi.org/10.1091/mbc.e16-08-0592.
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Planar cell polarity (PCP) regulates coordinated cellular polarity among neighboring cells to establish a polarity axis parallel to the plane of the tissue. Disruption in PCP results in a range of developmental anomalies and diseases. A key feature of PCP is the polarized and asymmetric localization of several membrane PCP proteins, which is essential to establish the polarity axis to orient cells coordinately. However, the machinery that regulates the asymmetric partition of PCP proteins remains largely unknown. In the present study, we show Van gogh-like 2 (Vangl2) in early and recycling endosomes as made evident by colocalization with diverse endosomal Rab proteins. Vangl2 biochemically interacts with adaptor protein-3 complex (AP-3). Using short hairpin RNA knockdown, we found that Vangl2 subcellular localization was modified in AP-3–depleted cells. Moreover, Vangl2 membrane localization within the cochlea is greatly reduced in AP-3–deficient mocha mice, which exhibit profound hearing loss. In inner ears from AP-3–deficient mocha mice, we observed PCP-dependent phenotypes, such as misorientation and deformation of hair cell stereociliary bundles and disorganization of hair cells characteristic of defects in convergent extension that is driven by PCP. These findings demonstrate a novel role of AP-3–mediated sorting mechanisms in regulating PCP proteins.
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Padmanabhan, Krishnanand, Hanna Grobe, Jonathan Cohen, Arad Soffer, Adnan Mahly, Orit Adir, Ronen Zaidel-Bar, and Chen Luxenburg. "Thymosin β4 is essential for adherens junction stability and epidermal planar cell polarity." Development 147, no. 23 (December 1, 2020): dev193425. http://dx.doi.org/10.1242/dev.193425.
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ABSTRACTPlanar cell polarity (PCP) is essential for tissue morphogenesis and homeostasis; however, the mechanisms that orchestrate the cell shape and packing dynamics required to establish PCP are poorly understood. Here, we identified a major role for the globular (G)-actin-binding protein thymosin-β4 (TMSB4X) in PCP establishment and cell adhesion in the developing epidermis. Depletion of Tmsb4x in mouse embryos hindered eyelid closure and hair-follicle angling owing to PCP defects. Tmsb4x depletion did not preclude epidermal cell adhesion in vivo or in vitro; however, it resulted in abnormal structural organization and stability of adherens junction (AJ) due to defects in filamentous (F)-actin and G-actin distribution. In cultured keratinocytes, TMSB4X depletion increased the perijunctional G/F-actin ratio and decreased G-actin incorporation into junctional actin networks, but it did not change the overall actin expression level or cellular F-actin content. A pharmacological treatment that increased the G/F-actin ratio and decreased actin polymerization mimicked the effects of Tmsb4x depletion on both AJs and PCP. Our results provide insights into the regulation of the actin pool and its involvement in AJ function and PCP establishment.
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Kim, Su Kyoung, Asako Shindo, Tae Joo Park, Edwin C. Oh, Srimoyee Ghosh, Ryan S. Gray, Richard A. Lewis, et al. "Planar Cell Polarity Acts Through Septins to Control Collective Cell Movement and Ciliogenesis." Science 329, no. 5997 (July 29, 2010): 1337–40. http://dx.doi.org/10.1126/science.1191184.
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The planar cell polarity (PCP) signaling pathway governs collective cell movements during vertebrate embryogenesis, and certain PCP proteins are also implicated in the assembly of cilia. The septins are cytoskeletal proteins controlling behaviors such as cell division and migration. Here, we identified control of septin localization by the PCP protein Fritz as a crucial control point for both collective cell movement and ciliogenesis in Xenopus embryos. We also linked mutations in human Fritz to Bardet-Biedl and Meckel-Gruber syndromes, a notable link given that other genes mutated in these syndromes also influence collective cell movement and ciliogenesis. These findings shed light on the mechanisms by which fundamental cellular machinery, such as the cytoskeleton, is regulated during embryonic development and human disease.
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Babayeva, Sima, Yulia Zilber, and Elena Torban. "Planar cell polarity pathway regulates actin rearrangement, cell shape, motility, and nephrin distribution in podocytes." American Journal of Physiology-Renal Physiology 300, no. 2 (February 2011): F549—F560. http://dx.doi.org/10.1152/ajprenal.00566.2009.
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Glomerular podocytes are highly polarized cells characterized by dynamic actin-based foot processes (FPs). Neighboring FPs form specialized junctions, slit diaphragms (SDs), which prevent passage of proteins into the ultrafiltrate. The SD protein complex is linked to cytoskeletal actin filaments and mutations in SD proteins lead to a dramatic change in cell morphology; proteinuria is accompanied by FP retraction and loss of SD structure. Thus, organization of the podocyte cytoskeleton is tightly linked to filtration barrier function. In a variety of cell systems, cytoskeleton arrangement is regulated by the planar cell polarity (PCP) pathway. PCP signals lead to the appearance of highly organized cellular structures that support directional cell movement and oriented cell division. Derangement of the PCP pathway causes neural tube defects and cystic kidney disease in mice. Here, we establish that the PCP pathway regulates the cytoskeleton of podocytes. We identify expression of core PCP proteins in mouse kidney sections and of PCP transcripts in murine and human cultured podocytes. The pathway is functional since Wnt5a causes redistribution of PCP proteins Dishevelled and Daam1. We also show that Wnt5a treatment changes podocyte morphology, alters nephrin distribution, increases the number of stress fibers, and increases cell motility. In reciprocal experiments, siRNA depletion of the core PCP gene Vangl2 reduced the number of cell projections and decreased stress fibers and cell motility. Finally, we demonstrate direct interactions between Vangl2 and the SD protein, MAGI-2. This suggests that the PCP pathway may be directly linked to organization of the SD as well as to regulation of podocyte cytoskeleton. Our observations indicate that PCP signaling may play an important role both in podocyte development and FP cytoskeleton dynamics.
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Zilber, Yulia, Sima Babayeva, Jung Hwa Seo, Jia Jia Liu, Steven Mootin, and Elena Torban. "The PCP effector Fuzzy controls cilial assembly and signaling by recruiting Rab8 and Dishevelled to the primary cilium." Molecular Biology of the Cell 24, no. 5 (March 2013): 555–65. http://dx.doi.org/10.1091/mbc.e12-06-0437.
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The planar cell polarity (PCP) pathway controls multiple cellular processes during vertebrate development. Recently the PCP pathway was implicated in ciliogenesis and in ciliary function. The primary cilium is an apically projecting solitary organelle that is generated via polarized intracellular trafficking. Because it acts as a signaling nexus, defects in ciliogenesis or cilial function cause multiple congenital anomalies in vertebrates. Loss of the PCP effector Fuzzy affects PCP signaling and formation of primary cilia; however, the mechanisms underlying these processes are largely unknown. Here we report that Fuzzy localizes to the basal body and ciliary axoneme and is essential for ciliogenesis by delivering Rab8 to the basal body and primary cilium. Fuzzy appears to control subcellular localization of the core PCP protein Dishevelled, recruiting it to Rab8-positive vesicles and to the basal body and cilium. We show that loss of Fuzzy results in inhibition of PCP signaling and hyperactivation of the canonical WNT pathway. We propose a mechanism by which Fuzzy participates in ciliogenesis and affects both canonical WNT and PCP signaling.
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Gault, William J., Patricio Olguin, Ursula Weber, and Marek Mlodzik. "Drosophila CK1-γ, gilgamesh, controls PCP-mediated morphogenesis through regulation of vesicle trafficking." Journal of Cell Biology 196, no. 5 (March 5, 2012): 605–21. http://dx.doi.org/10.1083/jcb.201107137.
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Cellular morphogenesis, including polarized outgrowth, promotes tissue shape and function. Polarized vesicle trafficking has emerged as a fundamental mechanism by which protein and membrane can be targeted to discrete subcellular domains to promote localized protrusions. Frizzled (Fz)/planar cell polarity (PCP) signaling orchestrates cytoskeletal polarization and drives morphogenetic changes in such contexts as the vertebrate body axis and external Drosophila melanogaster tissues. Although regulation of Fz/PCP signaling via vesicle trafficking has been identified, the interplay between the vesicle trafficking machinery and downstream terminal PCP-directed processes is less established. In this paper, we show that Drosophila CK1-γ/gilgamesh (gish) regulates the PCP-associated process of trichome formation through effects on Rab11-mediated vesicle recycling. Although the core Fz/PCP proteins dictate prehair formation broadly, CK1-γ/gish restricts nucleation to a single site. Moreover, CK1-γ/gish works in parallel with the Fz/PCP effector multiple wing hairs, which restricts prehair formation along the perpendicular axis to Gish. Our findings suggest that polarized Rab11-mediated vesicle trafficking regulated by CK1-γ is required for PCP-directed processes.
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Gajos-Michniewicz, Anna, and Malgorzata Czyz. "WNT Signaling in Melanoma." International Journal of Molecular Sciences 21, no. 14 (July 9, 2020): 4852. http://dx.doi.org/10.3390/ijms21144852.
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WNT-signaling controls important cellular processes throughout embryonic development and adult life, so any deregulation of this signaling can result in a wide range of pathologies, including cancer. WNT-signaling is classified into two categories: β-catenin-dependent signaling (canonical pathway) and β-catenin-independent signaling (non-canonical pathway), the latter can be further divided into WNT/planar cell polarity (PCP) and calcium pathways. WNT ligands are considered as unique directional growth factors that contribute to both cell proliferation and polarity. Origin of cancer can be diverse and therefore tissue-specific differences can be found in WNT-signaling between cancers, including specific mutations contributing to cancer development. This review focuses on the role of the WNT-signaling pathway in melanoma. The current view on the role of WNT-signaling in cancer immunity as well as a short summary of WNT pathway-related drugs under investigation are also provided.
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Tong, Wenxue, Yelin Zeng, Dick Ho Kiu Chow, Wai Yeung, Jiankun Xu, Yujie Deng, Shihui Chen, et al. "Wnt16 attenuates osteoarthritis progression through a PCP/JNK-mTORC1-PTHrP cascade." Annals of the Rheumatic Diseases 78, no. 4 (February 11, 2019): 551–61. http://dx.doi.org/10.1136/annrheumdis-2018-214200.
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ObjectivesWnt16 is implicated in bone fracture and bone mass accrual both in animals and humans. However, its functional roles and molecular mechanism in chondrocyte differentiation and osteoarthritis (OA) pathophysiology remain largely undefined. In this study, we analysed its mechanistic association and functional relationship in OA progression in chondrocyte lineage.MethodsThe role of Wnt16 during skeletal development was examined by Col2a1-Wnt16 transgenic mice and Wnt16fl/fl;Col2a1-Cre (Wnt16-cKO) mice. OA progression was assessed by micro-CT analysis and Osteoarthritis Research Society International score after anterior cruciate ligament transection (ACLT) surgery with Wnt16 manipulation by adenovirus intra-articular injection. The molecular mechanism was investigated in vitro using 3D chondrocyte pellet culture and biochemical analyses. Histological analysis was performed in mouse joints and human cartilage specimens.ResultsWnt16 overexpression in chondrocytes in mice significantly inhibited chondrocyte hypertrophy during skeletal development. Wnt16 deficiency exaggerated OA progression, whereas intra-articular injection of Ad-Wnt16 markedly attenuated ACLT-induced OA. Cellular and molecular analyses showed that, instead of β-catenin and calcium pathways, Wnt16 activated the planar cell polarity (PCP) and JNK pathway by interacting mainly with AP2b1, and to a lesser extend Ror2 and CD146, and subsequently induced PTHrP expression through phosphor-Raptor mTORC1 pathway.ConclusionsOur findings indicate that Wnt16 activates PCP/JNK and crosstalks with mTORC1-PTHrP pathway to inhibit chondrocyte hypertrophy. Our preclinical study suggests that Wnt16 may be a potential therapeutic target for OA treatment.
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Wiggan, O'Neil, and Paul A. Hamel. "Pax3 regulates morphogenetic cell behavior in vitro coincident with activation of a PCP/non-canonical Wnt-signaling cascade." Journal of Cell Science 115, no. 3 (February 1, 2002): 531–41. http://dx.doi.org/10.1242/jcs.115.3.531.
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Mutations to Pax3 and other Pax family genes in both mice and humans result in numerous tissue-specific morphological defects. Little is known, however, about the cellular and molecular mechanisms by which Pax genes regulate morphogenesis. We previously showed that Pax3 induces cell aggregation and a mesenchymal-to-epithelial transition in Saos-2 cells. We show here that Pax3-induced aggregates arise through the formation of distinct structures involving cell rearrangements and cell behaviors resembling those that occur during gastrulation and neurulation known as convergent extension. During these Pax3-induced processes, Dishevelled and Frizzled are localized to the actin cytoskeleton and both proteins coimmunoprecipitate focal adhesion components from detergent-insoluble cell fractions. We show further that these Pax3-induced cell movements are associated with activation of a Wnt-signaling cascade, resulting in induction and activation of c-Jun-N-terminal kinase/stress activated protein kinase (JNK/SAPK). All of these Wnt-signaling factors exhibit altered subcellular distribution in Pax3-expressing cells. In particular, we show the localization of JNK/SAPK to both the nucleus and to cytoplasmic multi-vesicular structures. These data show that Pax3 regulates morphogenetic cell behavior and that regulation of a conserved, planar cell polarity/noncanonical Wnt-signaling cascade entailing JNK activation is a function of Pax3 activity.
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Shin, Jean, Shaojie Ma, Edith Hofer, Yash Patel, Daniel E. Vosberg, Steven Tilley, Gennady V. Roshchupkin, et al. "Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes." Cerebral Cortex 30, no. 7 (March 20, 2020): 4121–39. http://dx.doi.org/10.1093/cercor/bhaa035.
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Abstract We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade—albeit in a very limited manner—to behaviors as complex as the choice of one’s occupation.
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Menck, Kerstin, Saskia Heinrichs, Cornelia Baden, and Annalen Bleckmann. "The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention." Cells 10, no. 1 (January 12, 2021): 142. http://dx.doi.org/10.3390/cells10010142.
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The WNT pathway is one of the major signaling cascades frequently deregulated in human cancer. While research had initially focused on signal transduction centered on β-catenin as a key effector activating a pro-tumorigenic transcriptional response, nowadays it is known that WNT ligands can also induce a multitude of β-catenin-independent cellular pathways. Traditionally, these comprise WNT/planar cell polarity (PCP) and WNT/Ca2+ signaling. In addition, signaling via the receptor tyrosine kinase-like orphan receptors (RORs) has gained increasing attention in cancer research due to their overexpression in a multitude of tumor entities. Active WNT/ROR signaling has been linked to processes driving tumor development and progression, such as cell proliferation, survival, invasion, or therapy resistance. In adult tissue, the RORs are largely absent, which has spiked the interest in them for targeted cancer therapy. Promising results in preclinical and initial clinical studies are beginning to unravel the great potential of such treatment approaches. In this review, we summarize seminal findings on the structure and expression of the RORs in cancer, their downstream signaling, and its output in regard to tumor cell function. Furthermore, we present the current clinical anti-ROR treatment strategies and discuss the state-of-the-art, as well as the challenges of the different approaches.
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Nguyen, Genevieve. "Renin, (pro)renin and receptor: an update." Clinical Science 120, no. 5 (November 19, 2010): 169–78. http://dx.doi.org/10.1042/cs20100432.
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PRR [(pro)renin receptor] was named after its biological characteristics, namely the binding of renin and of its inactive precursor prorenin, that triggers intracellular signalling involving ERK (extracellular-signal-regulated kinase) 1/2. However the gene encoding for PRR is named ATP6ap2 (ATPase 6 accessory protein 2) because PRR was initially found as a truncated form co-purifying with V-ATPase (vacuolar H+-ATPase). There are now data showing that this interaction is not only physical, but also functional in the kidney and the heart. However, the newest and most fascinating development of PRR is its involvement in both the canonical Wnt/β-catenin and non-canonical Wnt/PCP (planar cell polarity) pathways, which are essential for adult and embryonic stem cell biology, embryonic development and disease, including cancer. In the Wnt/β-catenin pathway, it has been shown that PRR acts as an adaptor between the Wnt receptor LRP5/6 (low-density lipoprotein receptor-related protein 5/6) and Fz (frizzled) and that the proton gradient generated by the V-ATPase in endosomes is necessary for LRP5/6 phosphorylation and β-catenin activation. In the Wnt/PCP pathway, PRR binds to Fz and controls its asymetrical subcellular distribution and therefore the polarization of the cells in a plane of a tissue. These essential cellular functions of PRR are independent of renin and open new avenues on the pathophysiological role of PRR. The present review will summarize our knowledge of (pro)renin-dependent functions of PRR and will discuss the newly recognized functions of PRR related to the V-ATPase and to Wnt signalling.
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Stevens, Payton D., Emily Sall, Alex Zhong, Galen Hostetter, Zachary Madaj, Jennifer Thalappillil, Alexander Dobin, Youngkyu Park, David A. Tuveson, and Bart O. Williams. "Abstract 1572: FZD6 and RYK, non-canonical Wnt receptors in pancreatic cancer progression." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1572. http://dx.doi.org/10.1158/1538-7445.am2022-1572.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) has a grim prognosis with 5-year patient survival of less than 10%. Development of effective therapeutics has been hampered by the PDAC tumor microenvironment (TME), which contains dense desmoplastic stroma that likely impedes the ability of therapies to reach the tumor cells. We have found that aggressive, “basal-like” human PDAC tumors have high expression of proteins involved in planar-cell-polarity (PCP), a type of non-canonical Wnt signaling. We show that the increased expression of the PCP genes, including the putative non-canonical Wnt ligand, Wnt5a, the Frizzled 6 (FZD6) Wnt receptor, and RYK co-receptor negatively impact patient prognosis. Using a panel of FZD6 knock-down pancreatic cell lines, we show that loss of FZD6 increases expression of the epithelial marker, E-cadherin, and decreases cellular motility in Transwell assays. We also find that loss of Fzd6 dramatically inhibits tumor progression in two mouse models of PDAC, with a pronounced change to the TME; including the cancer-associated fibroblasts (CAFs) and immune cells. Blinded histologic pathology review of tumor and immune cell infiltrates, by H&E and alphaSMA staining, suggests that the CAF cell population is altered. We propose this is the cause of the looser stroma surrounding the tumors after Fzd6 loss, which also results in an increased abundance of CD4 and CD8 positive T cells surrounding and within the tumors. Additionally, immunohistochemical staining for other PCP proteins within the pancreatic tumors lacking Fzd6 suggests that Fzd6 loss reduces PCP-component protein levels. We hypothesize that the loss of Fzd6 reduces tumor cell EMT and PCP signaling, while the loose stroma allows more immune cells that further slow tumor growth and progression. We have also examined the expression of PCP proteins in a novel orthotopic xenotransplantation model of PDAC, intraductally grafted organoids (IGO). IGO is a powerful tool to study PDAC as the intraductal tumors that develop recapitulate patient to patient heterogeneity while displaying features of either classical or basal-like PDAC subtypes. FZD6 and RYK are both more highly expressed in the IGO basal-like tumors than the classical type. Introduction of fast-growing, basal-like human tumors into the murine pancreas also resulted in a TME that produces more Wnt5a, when compared to the stroma surrounding tumors formed by injecting the classical subtype. Taken together, we believe we have identified a Wnt5a/Fzd6 driven PCP-like signaling pathway that makes tumors more mesenchymal-like, and results in PDAC tumor progression and worse patient prognosis. Citation Format: Payton D. Stevens, Emily Sall, Alex Zhong, Galen Hostetter, Zachary Madaj, Jennifer Thalappillil, Alexander Dobin, Youngkyu Park, David A. Tuveson, Bart O. Williams. FZD6 and RYK, non-canonical Wnt receptors in pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1572.
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Kacker, Sandeep, Varuneshwar Parsad, Naveen Singh, Daria Hordiichuk, Stacy Alvarez, Mahnoor Gohar, Anshu Kacker, and Sunil Kumar Rai. "Planar Cell Polarity Signaling: Coordinated Crosstalk for Cell Orientation." Journal of Developmental Biology 12, no. 2 (April 29, 2024): 12. http://dx.doi.org/10.3390/jdb12020012.
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The planar cell polarity (PCP) system is essential for positioning cells in 3D networks to establish the proper morphogenesis, structure, and function of organs during embryonic development. The PCP system uses inter- and intracellular feedback interactions between components of the core PCP, characterized by coordinated planar polarization and asymmetric distribution of cell populations inside the cells. PCP signaling connects the anterior–posterior to left–right embryonic plane polarity through the polarization of cilia in the Kupffer’s vesicle/node in vertebrates. Experimental investigations on various genetic ablation-based models demonstrated the functions of PCP in planar polarization and associated genetic disorders. This review paper aims to provide a comprehensive overview of PCP signaling history, core components of the PCP signaling pathway, molecular mechanisms underlying PCP signaling, interactions with other signaling pathways, and the role of PCP in organ and embryonic development. Moreover, we will delve into the negative feedback regulation of PCP to maintain polarity, human genetic disorders associated with PCP defects, as well as challenges associated with PCP.
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Chen, Haiqi, Dolores D. Mruk, Wing-yee Lui, Chris K. C. Wong, Will M. Lee, and C. Yan Cheng. "Cell polarity and planar cell polarity (PCP) in spermatogenesis." Seminars in Cell & Developmental Biology 81 (September 2018): 71–77. http://dx.doi.org/10.1016/j.semcdb.2017.09.008.
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Landin Malt, Andre, Zachary Dailey, Julia Holbrook-Rasmussen, Yuqiong Zheng, Arielle Hogan, Quansheng Du, and Xiaowei Lu. "Par3 is essential for the establishment of planar cell polarity of inner ear hair cells." Proceedings of the National Academy of Sciences 116, no. 11 (February 27, 2019): 4999–5008. http://dx.doi.org/10.1073/pnas.1816333116.
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In the inner ear sensory epithelia, stereociliary hair bundles atop sensory hair cells are mechanosensory apparatus with planar polarized structure and orientation. This is established during development by the concerted action of tissue-level, intercellular planar cell polarity (PCP) signaling and a hair cell-intrinsic, microtubule-mediated machinery. However, how various polarity signals are integrated during hair bundle morphogenesis is poorly understood. Here, we show that the conserved cell polarity protein Par3 is essential for planar polarization of hair cells. Par3 deletion in the inner ear disrupted cochlear outgrowth, hair bundle orientation, kinocilium positioning, and basal body planar polarity, accompanied by defects in the organization and cortical attachment of hair cell microtubules. Genetic mosaic analysis revealed that Par3 functions both cell-autonomously and cell-nonautonomously to regulate kinocilium positioning and hair bundle orientation. At the tissue level, intercellular PCP signaling regulates the asymmetric localization of Par3, which in turn maintains the asymmetric localization of the core PCP protein Vangl2. Mechanistically, Par3 interacts with and regulates the localization of Tiam1 and Trio, which are guanine nucleotide exchange factors (GEFs) for Rac, thereby stimulating Rac-Pak signaling. Finally, constitutively active Rac1 rescued the PCP defects in Par3-deficient cochleae. Thus, a Par3–GEF–Rac axis mediates both tissue-level and hair cell-intrinsic PCP signaling.
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Rocque, Brittany, and Elena Torban. "Planar Cell Polarity Pathway in Kidney Development and Function." Advances in Nephrology 2015 (February 25, 2015): 1–15. http://dx.doi.org/10.1155/2015/764682.
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The evolutionarily conserved planar cell polarity (PCP) signaling pathway controls tissue polarity within the plane orthogonal to the apical-basal axis. PCP was originally discovered in Drosophila melanogaster where it is required for the establishment of a uniform pattern of cell structures and appendages. In vertebrates, including mammals, the PCP pathway has been adapted to control various morphogenetic processes that are critical for tissue and organ development. These include convergent extension (crucial for neural tube closure and cochlear duct development) and oriented cell division (needed for tubular elongation), ciliary tilting that enables directional fluid flow, and other processes. Recently, strong evidence has emerged to implicate the PCP pathway in vertebrate kidney development. In this review, we will describe the experimental data revealing the role of PCP signaling in nephrogenesis and kidney disease.
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Kim, Sun K., Siwei Zhang, Michael E. Werner, Eva J. Brotslaw, Jennifer W. Mitchell, Mohamed M. Altabbaa, and Brian J. Mitchell. "CLAMP/Spef1 regulates planar cell polarity signaling and asymmetric microtubule accumulation in the Xenopus ciliated epithelia." Journal of Cell Biology 217, no. 5 (March 7, 2018): 1633–41. http://dx.doi.org/10.1083/jcb.201706058.
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Most epithelial cells polarize along the axis of the tissue, a feature known as planar cell polarity (PCP). The initiation of PCP requires cell–cell signaling via the noncanonical Wnt/PCP pathway. Additionally, changes in the cytoskeleton both facilitate and reflect this polarity. We have identified CLAMP/Spef1 as a novel regulator of PCP signaling. In addition to decorating microtubules (MTs) and the ciliary rootlet, a pool of CLAMP localizes at the apical cell cortex. Depletion of CLAMP leads to the loss of PCP protein asymmetry, defects in cilia polarity, and defects in the angle of cell division. Additionally, depletion of CLAMP leads to a loss of the atypical cadherin-like molecule Celrs2, suggesting that CLAMP facilitates the stabilization of junctional interactions responsible for proper PCP protein localization. Depletion of CLAMP also affects the polarized organization of MTs. We hypothesize that CLAMP facilitates the establishment of cell polarity and promotes the asymmetric accumulation of MTs downstream of the establishment of proper PCP.
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Chen, Haiqi, and C. Yan Cheng. "Planar cell polarity (PCP) proteins and spermatogenesis." Seminars in Cell & Developmental Biology 59 (November 2016): 99–109. http://dx.doi.org/10.1016/j.semcdb.2016.04.010.
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Wu, Gang, Jiao Ge, Xupei Huang, Yimin Hua, and Dezhi Mu. "Planar Cell Polarity Signaling Pathway in Congenital Heart Diseases." Journal of Biomedicine and Biotechnology 2011 (2011): 1–8. http://dx.doi.org/10.1155/2011/589414.
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Congenital heart disease (CHD) is a common cardiac disorder in humans. Despite many advances in the understanding of CHD and the identification of many associated genes, the fundamental etiology for the majority of cases remains unclear. The planar cell polarity (PCP) signaling pathway, responsible for tissue polarity inDrosophilaand gastrulation movements and cardiogenesis in vertebrates, has been shown to play multiple roles during cardiac differentiation and development. The disrupted function of PCP signaling is connected to some CHDs. Here, we summarize our current understanding of how PCP factors affect the pathogenesis of CHD.
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Najarro, Elvis Huarcaya, Jennifer Huang, Adrian Jacobo, Lee A. Quiruz, Nicolas Grillet, and Alan G. Cheng. "Dual regulation of planar polarization by secreted Wnts and Vangl2 in the developing mouse cochlea." Development 147, no. 19 (September 9, 2020): dev191981. http://dx.doi.org/10.1242/dev.191981.
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ABSTRACTPlanar cell polarity (PCP) proteins localize asymmetrically to instruct cell polarity within the tissue plane, with defects leading to deformities of the limbs, neural tube and inner ear. Wnt proteins are evolutionarily conserved polarity cues, yet Wnt mutants display variable PCP defects; thus, how Wnts regulate PCP remains unresolved. Here, we have used the developing cochlea as a model system to show that secreted Wnts regulate PCP through polarizing a specific subset of PCP proteins. Conditional deletion of Wntless or porcupine, both of which are essential for secretion of Wnts, caused misrotated sensory cells and shortened cochlea – both hallmarks of PCP defects. Wntless-deficient cochleae lacked the polarized PCP components dishevelled 1/2 and frizzled 3/6, while other PCP proteins (Vangl1/2, Celsr1 and dishevelled 3) remained localized. We identified seven Wnt paralogues, including the major PCP regulator Wnt5a, which was, surprisingly, dispensable for planar polarization in the cochlea. Finally, Vangl2 haploinsufficiency markedly accentuated sensory cell polarization defects in Wntless-deficient cochlea. Together, our study indicates that secreted Wnts and Vangl2 coordinate to ensure proper tissue polarization during development.
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Vladar, Eszter K., and Melanie Königshoff. "Noncanonical Wnt planar cell polarity signaling in lung development and disease." Biochemical Society Transactions 48, no. 1 (February 25, 2020): 231–43. http://dx.doi.org/10.1042/bst20190597.
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The planar cell polarity (PCP) signaling pathway is a potent developmental regulator of directional cell behaviors such as migration, asymmetric division and morphological polarization that are critical for shaping the body axis and the complex three-dimensional architecture of tissues and organs. PCP is considered a noncanonical Wnt pathway due to the involvement of Wnt ligands and Frizzled family receptors in the absence of the beta-catenin driven gene expression observed in the canonical Wnt cascade. At the heart of the PCP mechanism are protein complexes capable of generating molecular asymmetries within cells along a tissue-wide axis that are translated into polarized actin and microtubule cytoskeletal dynamics. PCP has emerged as an important regulator of developmental, homeostatic and disease processes in the respiratory system. It acts along other signaling pathways to create the elaborately branched structure of the lung by controlling the directional protrusive movements of cells during branching morphogenesis. PCP operates in the airway epithelium to establish and maintain the orientation of respiratory cilia along the airway axis for anatomically directed mucociliary clearance. It also regulates the establishment of the pulmonary vasculature. In adult tissues, PCP dysfunction has been linked to a variety of chronic lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, and idiopathic pulmonary arterial hypertension, stemming chiefly from the breakdown of proper tissue structure and function and aberrant cell migration during regenerative wound healing. A better understanding of these (impaired) PCP mechanisms is needed to fully harness the therapeutic opportunities of targeting PCP in chronic lung diseases.
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Li, Ling, Diana Zepeda-Orozco, Vishal Patel, Phu Truong, Courtney M. Karner, Thomas J. Carroll, and Fangming Lin. "Aberrant planar cell polarity induced by urinary tract obstruction." American Journal of Physiology-Renal Physiology 297, no. 6 (December 2009): F1526—F1533. http://dx.doi.org/10.1152/ajprenal.00318.2009.
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Flow sensing by primary cilia of the epithelial cells is involved in cystogenesis in polycystic kidney disease. We investigate whether a similar mechanism applies to the pathogenesis of cyst-like tubular dilatation induced by ureteral obstruction in mice. Robust proliferation occurs in the obstructed tubules when urine flow is interrupted as well as in the repairing tubules when urine flow is reestablished after relief of the obstruction, suggesting a urine flow-independent mechanism of proliferation. In the urothelium, proliferation is only detected above the obstruction, although urine flow ceased both above and below the obstruction. Our results support mechanical strain- rather than flow-mediated proliferation in obstructive uropathy. To understand the mechanism of cell proliferation leading to increased tubular diameter in cyst-like tubular dilatation, we examine planar cell polarity (PCP), which is necessary for oriented cell division and maintenance of tubular diameter. In dilated tubules, the orientation of cell division is randomized, atypical PKC (aPKC) is mislocalized, and the pattern of the expression of a core PCP protein, Frizzled3 (Fz3), is altered. In addition, the level of Fz3 expression is increased. These results indicate that aberrant PCP may contribute to cyst-like tubular dilatation in obstructive uropathy. Interestingly, the orientation of cell division, localization of aPKC, and Fz3 expression return to normal when obstruction is relieved, which suggest a role of normal PCP signaling in tubular repair.
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Pietra, Stefano, KangBo Ng, Peter A. Lawrence, and José Casal. "Planar cell polarity in the larval epidermis of Drosophila and the role of microtubules." Open Biology 10, no. 12 (December 2020): 200290. http://dx.doi.org/10.1098/rsob.200290.
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We investigate planar cell polarity (PCP) in the Drosophila larval epidermis. The intricate pattern of denticles depends on only one system of PCP, the Dachsous/Fat system. Dachsous molecules in one cell bind to Fat molecules in a neighbour cell to make intercellular bridges. The disposition and orientation of these Dachsous–Fat bridges allows each cell to compare two neighbours and point its denticles towards the neighbour with the most Dachsous. Measurements of the amount of Dachsous reveal a peak at the back of the anterior compartment of each segment. Localization of Dachs and orientation of ectopic denticles help reveal the polarity of every cell. We discuss whether these findings support our gradient model of Dachsous activity. Several groups have proposed that Dachsous and Fat fix the direction of PCP via oriented microtubules that transport PCP proteins to one side of the cell. We test this proposition in the larval cells and find that most microtubules grow perpendicularly to the axis of PCP. We find no meaningful bias in the polarity of microtubules aligned close to that axis. We also reexamine published data from the pupal abdomen and find no evidence supporting the hypothesis that microtubular orientation draws the arrow of PCP.
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Li, Linxi, Huitao Li, Lingling Wang, Siwen Wu, Lixiu Lv, Anam Tahir, Xiang Xiao, et al. "Role of cell polarity and planar cell polarity (PCP) proteins in spermatogenesis." Critical Reviews in Biochemistry and Molecular Biology 55, no. 1 (January 2, 2020): 71–87. http://dx.doi.org/10.1080/10409238.2020.1742091.
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Voutsadakis, Ioannis A. "Molecular Alterations and Putative Therapeutic Targeting of Planar Cell Polarity Proteins in Breast Cancer." Journal of Clinical Medicine 12, no. 2 (January 4, 2023): 411. http://dx.doi.org/10.3390/jcm12020411.
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Background: Treatment and outcomes of breast cancer, one of the most prevalent female cancers, have improved in recent decades. However, metastatic breast cancer remains incurable in most cases, and new therapies are needed to ameliorate prognosis. Planar cell polarity (PCP) is a characteristic of epithelial cells that form layers and is integral to the communication of these cells with neighboring cells. Dysfunction of PCP is observed in cancers and may confer a targetable vulnerability. Methods: The breast cancer cohorts from The Cancer Genome Atlas (TCGA) and the METABRIC study were interrogated for molecular alterations in genes of the PCP pathway. The groups with the most prevalent alterations were characterized, and survival was compared with counterparts not possessing PCP alterations. Breast cancer cell lines with PCP alterations from the Cancer Cell Line Encyclopedia (CCLE) were interrogated for sensitivity to drugs affecting PCP. Results: Among genes of the PCP pathway, VANGL2, NOS1AP and SCRIB display amplifications in a sizable minority of breast cancers. Concomitant up-regulation at the mRNA level can be observed mostly in basal cancers, but it does not correlate well with the amplification status of the genes, as it can also be observed in non-amplified cases. In an exploration of cell line models, two of the four breast cancer cell line models with amplifications in VANGL2, NOS1AP and SCRIB display sensitivity to drugs inhibiting acyl-transferase porcupine interfering with the WNT pathway. This sensitivity suggests a possible therapeutic role of these inhibitors in cancers bearing the amplifications. Conclusion: Molecular alterations in PCP genes can be observed in breast cancers with a predilection for the basal sub-type. An imperfect correlation of copy number alterations with mRNA expression suggests that post-translational modifications are important in PCP regulation. Inhibitors of acyl-transferase porcupine may be rational candidates for combination therapy development in PCP-altered breast cancers.
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Miyagi, Chiemi, Susumu Yamashita, Yusuke Ohba, Hisayoshi Yoshizaki, Michiyuki Matsuda, and Toshio Hirano. "STAT3 noncell-autonomously controls planar cell polarity during zebrafish convergence and extension." Journal of Cell Biology 166, no. 7 (September 27, 2004): 975–81. http://dx.doi.org/10.1083/jcb.200403110.
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Zebrafish signal transducer and activator of transcription 3 (STAT3) controls the cell movements during gastrulation. Here, we show that noncell-autonomous activity of STAT3 signaling in gastrula organizer cells controls the polarity of neighboring cells through Dishevelled-RhoA signaling in the Wnt-planar cell polarity (Wnt-PCP) pathway. In STAT3-depleted embryos, although all the known molecules in the Wnt-PCP pathway were expressed normally, the RhoA activity in lateral mesendodermal cells was down-regulated, resulting in severe cell polarization defects in convergence and extension movements identical to Strabismus-depleted embryos. Cell-autonomous activation of Wnt-PCP signaling by ΔN-dishevelled rescued the defect in cell elongation, but not the orientation of lateral mesendodermal cells in STAT3-depleted embryos. The defect in the orientation could be rescued by transplantation of shield cells having noncell-autonomous activity of STAT3 signaling. These results suggest that the cells undergoing convergence and extension movement may sense the gradient of signaling molecules, which are expressed in gastrula organizer by STAT3 and noncell-autonomously activate PCP signaling in neighboring cells during zebrafish gastrulation.
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Siletti, Kimberly, Basile Tarchini, and A. J. Hudspeth. "Daple coordinates organ-wide and cell-intrinsic polarity to pattern inner-ear hair bundles." Proceedings of the National Academy of Sciences 114, no. 52 (December 11, 2017): E11170—E11179. http://dx.doi.org/10.1073/pnas.1716522115.
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The establishment of planar polarization by mammalian cells necessitates the integration of diverse signaling pathways. In the inner ear, at least two systems regulate the planar polarity of sensory hair bundles. The core planar cell polarity (PCP) proteins coordinate the orientations of hair cells across the epithelial plane. The cell-intrinsic patterning of hair bundles is implemented independently by the G protein complex classically known for orienting the mitotic spindle. Although the primary cilium also participates in each of these pathways, its role and the integration of the two systems are poorly understood. We show that Dishevelled-associating protein with a high frequency of leucine residues (Daple) interacts with PCP and cell-intrinsic signals. Regulated by the cell-intrinsic pathway, Daple is required to maintain the polarized distribution of the core PCP protein Dishevelled and to position the primary cilium at the abneural edge of the apical surface. Our results suggest that the primary cilium or an associated structure influences the domain of cell-intrinsic signals that shape the hair bundle. Daple is therefore essential to orient and pattern sensory hair bundles.
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Guillabert-Gourgues, Aude, Beatrice Jaspard-Vinassa, Marie-Lise Bats, Raj N. Sewduth, Nathalie Franzl, Claire Peghaire, Sylvie Jeanningros, et al. "Kif26b controls endothelial cell polarity through the Dishevelled/Daam1-dependent planar cell polarity–signaling pathway." Molecular Biology of the Cell 27, no. 6 (March 15, 2016): 941–53. http://dx.doi.org/10.1091/mbc.e14-08-1332.
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Angiogenesis involves the coordinated growth and migration of endothelial cells (ECs) toward a proangiogenic signal. The Wnt planar cell polarity (PCP) pathway, through the recruitment of Dishevelled (Dvl) and Dvl-associated activator of morphogenesis (Daam1), has been proposed to regulate cell actin cytoskeleton and microtubule (MT) reorganization for oriented cell migration. Here we report that Kif26b—a kinesin—and Daam1 cooperatively regulate initiation of EC sprouting and directional migration via MT reorganization. First, we find that Kif26b is recruited within the Dvl3/Daam1 complex. Using a three-dimensional in vitro angiogenesis assay, we show that Kif26b and Daam1 depletion impairs tip cell polarization and destabilizes extended vascular processes. Kif26b depletion specifically alters EC directional migration and mislocalized MT organizing center (MTOC)/Golgi and myosin IIB cell rear enrichment. Therefore the cell fails to establish a proper front–rear polarity. Of interest, Kif26b ectopic expression rescues the siDaam1 polarization defect phenotype. Finally, we show that Kif26b functions in MT stabilization, which is indispensable for asymmetrical cell structure reorganization. These data demonstrate that Kif26b, together with Dvl3/Daam1, initiates cell polarity through the control of PCP signaling pathway–dependent activation.
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Ganner, Athina, Soeren Lienkamp, and Gerd Walz. "Planar cell polarity (PCP) and Wnt signaling in renal disease." Drug Discovery Today: Disease Mechanisms 10, no. 3-4 (December 2013): e159-e166. http://dx.doi.org/10.1016/j.ddmec.2013.12.001.
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Humphries, Ashley C., Claudia Molina-Pelayo, Parijat Sil, C. Clayton Hazelett, Danelle Devenport, and Marek Mlodzik. "A Van Gogh/Vangl tyrosine phosphorylation switch regulates its interaction with core Planar Cell Polarity factors Prickle and Dishevelled." PLOS Genetics 19, no. 7 (July 18, 2023): e1010849. http://dx.doi.org/10.1371/journal.pgen.1010849.
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Epithelial tissues can be polarized along two axes: in addition to apical-basal polarity they are often also polarized within the plane of the epithelium, known as planar cell polarity (PCP). PCP depends upon the conserved Wnt/Frizzled (Fz) signaling factors, including Fz itself and Van Gogh (Vang/Vangl in mammals). Here, taking advantage of the complementary features of Drosophila wing and mouse skin PCP establishment, we dissect how Vang/Vangl phosphorylation on a specific conserved tyrosine residue affects its interaction with two cytoplasmic core PCP factors, Dishevelled (Dsh/Dvl1-3 in mammals) and Prickle (Pk/Pk1-3). We demonstrate that Pk and Dsh/Dvl bind to Vang/Vangl in an overlapping region centered around this tyrosine. Strikingly, Vang/Vangl phosphorylation promotes its binding to Prickle, a key effector of the Vang/Vangl complex, and inhibits its interaction with Dishevelled. Thus phosphorylation of this tyrosine appears to promote the formation of the mature Vang/Vangl-Pk complex during PCP establishment and conversely it inhibits the Vang interaction with the antagonistic effector Dishevelled. Intriguingly, the phosphorylation state of this tyrosine might thus serve as a switch between transient interactions with Dishevelled and stable formation of Vang-Pk complexes during PCP establishment.
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Artus, Cédric, Fabienne Glacial, Kayathiri Ganeshamoorthy, Nicole Ziegler, Maeva Godet, Thomas Guilbert, Stefan Liebner, and Pierre-Olivier Couraud. "The Wnt/Planar Cell Polarity Signaling Pathway Contributes to the Integrity of Tight Junctions in Brain Endothelial Cells." Journal of Cerebral Blood Flow & Metabolism 34, no. 3 (December 18, 2013): 433–40. http://dx.doi.org/10.1038/jcbfm.2013.213.
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Wnt morphogens released by neural precursor cells were recently reported to control blood–brain barrier (BBB) formation during development. Indeed, in mouse brain endothelial cells, activation of the Wnt/ β-catenin signaling pathway, also known as the canonical Wnt pathway, was shown to stabilize endothelial tight junctions (TJs) through transcriptional regulation of the expression of TJ proteins. Because Wnt proteins activate several distinct β-catenin-dependent and independent signaling pathways, this study was designed to assess whether the noncanonical Wnt/Par/aPKC planar cell polarity (PCP) pathway might also control TJ integrity in brain endothelial cells. First we established, in the hCMEC/D3 human brain endothelial cell line, that the Par/aPKC PCP complex colocalizes with TJs and controls apicobasal polarization. Second, using an siRNA approach, we showed that the Par/aPKC PCP complex regulates TJ stability and reassembling after osmotic shock. Finally, we provided evidence that Wnt5a signals in hCMEC/D3 cells through activation of the Par/aPKC PCP complex, independently of the Wnt canonical β-catenin-dependent pathway and significantly contributes to TJ integrity and endothelial apicobasal polarity. In conclusion, this study suggests that the Wnt/Par/aPKC PCP pathway, in addition to the Wnt/ β-catenin canonical pathway, is a key regulator of the BBB.
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Collu, Giovanna M., and Marek Mlodzik. "Planar Polarity: Converting a Morphogen Gradient into Cellular Polarity." Current Biology 25, no. 9 (May 2015): R372—R374. http://dx.doi.org/10.1016/j.cub.2015.03.011.
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Brooks, Eric R., and John B. Wallingford. "Control of vertebrate intraflagellar transport by the planar cell polarity effector Fuz." Journal of Cell Biology 198, no. 1 (July 9, 2012): 37–45. http://dx.doi.org/10.1083/jcb.201204072.
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Cilia play key roles in development and homeostasis, and defects in cilia structure or function lead to an array of human diseases. Ciliogenesis is accomplished by the intraflagellar transport (IFT) system, a set of proteins governing bidirectional transport of cargoes within ciliary axonemes. In this paper, we present a novel platform for in vivo analysis of vertebrate IFT dynamics. Using this platform, we show that the planar cell polarity (PCP) effector Fuz was required for normal IFT dynamics in vertebrate cilia, the first evidence directly linking PCP to the core machinery of ciliogenesis. Further, we show that Fuz played a specific role in trafficking of retrograde, but not anterograde, IFT proteins. These data place Fuz in the small group of known IFT effectors outside the core machinery and, additionally, identify Fuz as a novel cytoplasmic effector that differentiates between the retrograde and anterograde IFT complexes.
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Wang, Irene-Yanran, Chen-Fang Chung, Sima Babayeva, Tamara Sogomonian, and Elena Torban. "Loss of Planar Cell Polarity Effector Fuzzy Causes Renal Hypoplasia by Disrupting Several Signaling Pathways." Journal of Developmental Biology 10, no. 1 (December 23, 2021): 1. http://dx.doi.org/10.3390/jdb10010001.
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In vertebrates, the planar cell polarity (PCP) pathway regulates tissue morphogenesis during organogenesis, including the kidney. Mutations in human PCP effector proteins have been associated with severe syndromic ciliopathies. Importantly, renal hypoplasia has been reported in some patients. However, the developmental disturbance that causes renal hypoplasia is unknown. Here, we describe the early onset of profound renal hypoplasia in mice homozygous for null mutation of the PCP effector gene, Fuzzy. We found that this phenotype is caused by defective branching morphogenesis of the ureteric bud (UB) in the absence of defects in nephron progenitor specification or in early steps of nephrogenesis. By using various experimental approaches, we show that the loss of Fuzzy affects multiple signaling pathways. Specifically, we found mild involvement of GDNF/c-Ret pathway that drives UB branching. We noted the deficient expression of molecules belonging to the Bmp, Fgf and Shh pathways. Analysis of the primary cilia in the UB structures revealed a significant decrease in ciliary length. We conclude that renal hypoplasia in the mouse Fuzzy mutants is caused by defective UB branching associated with dysregulation of ciliary and non-ciliary signaling pathways. Our work suggests a PCP effector-dependent pathogenetic mechanism that contributes to renal hypoplasia in mice and humans.
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Findlay, Amy S., D. Alessio Panzica, Petr Walczysko, Amy B. Holt, Deborah J. Henderson, John D. West, Ann M. Rajnicek, and J. Martin Collinson. "The core planar cell polarity gene, Vangl2 , directs adult corneal epithelial cell alignment and migration." Royal Society Open Science 3, no. 10 (October 2016): 160658. http://dx.doi.org/10.1098/rsos.160658.
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This study shows that the core planar cell polarity (PCP) genes direct the aligned cell migration in the adult corneal epithelium, a stratified squamous epithelium on the outer surface of the vertebrate eye. Expression of multiple core PCP genes was demonstrated in the adult corneal epithelium. PCP components were manipulated genetically and pharmacologically in human and mouse corneal epithelial cells in vivo and in vitro . Knockdown of VANGL2 reduced the directional component of migration of human corneal epithelial (HCE) cells without affecting speed. It was shown that signalling through PCP mediators, dishevelled, dishevelled-associated activator of morphogenesis and Rho-associated protein kinase directs the alignment of HCE cells by affecting cytoskeletal reorganization. Cells in which VANGL2 was disrupted tended to misalign on grooved surfaces and migrate across, rather than parallel to the grooves. Adult corneal epithelial cells in which Vangl2 had been conditionally deleted showed a reduced rate of wound-healing migration. Conditional deletion of Vangl2 in the mouse corneal epithelium ablated the normal highly stereotyped patterns of centripetal cell migration in vivo from the periphery (limbus) to the centre of the cornea. Corneal opacity owing to chronic wounding is a major cause of degenerative blindness across the world, and this study shows that Vangl2 activity is required for directional corneal epithelial migration.
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Li, Linxi, Ying Gao, Haiqi Chen, Tito Jesus, Elizabeth Tang, Nan Li, Qingquan Lian, Ren-shan Ge, and C. Yan Cheng. "Cell polarity, cell adhesion, and spermatogenesis: role of cytoskeletons." F1000Research 6 (August 25, 2017): 1565. http://dx.doi.org/10.12688/f1000research.11421.1.
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In the rat testis, studies have shown that cell polarity, in particular spermatid polarity, to support spermatogenesis is conferred by the coordinated efforts of the Par-, Crumbs-, and Scribble-based polarity complexes in the seminiferous epithelium. Furthermore, planar cell polarity (PCP) is conferred by PCP proteins such as Van Gogh-like 2 (Vangl2) in the testis. On the other hand, cell junctions at the Sertoli cell–spermatid (steps 8–19) interface are exclusively supported by adhesion protein complexes (for example, α6β1-integrin-laminin-α3,β3,γ3 and nectin-3-afadin) at the actin-rich apical ectoplasmic specialization (ES) since the apical ES is the only anchoring device in step 8–19 spermatids. For cell junctions at the Sertoli cell–cell interface, they are supported by adhesion complexes at the actin-based basal ES (for example, N-cadherin-β-catenin and nectin-2-afadin), tight junction (occludin-ZO-1 and claudin 11-ZO-1), and gap junction (connexin 43-plakophilin-2) and also intermediate filament-based desmosome (for example, desmoglein-2-desmocollin-2). In short, the testis-specific actin-rich anchoring device known as ES is crucial to support spermatid and Sertoli cell adhesion. Accumulating evidence has shown that the Par-, Crumbs-, and Scribble-based polarity complexes and the PCP Vangl2 are working in concert with actin- or microtubule-based cytoskeletons (or both) and these polarity (or PCP) protein complexes exert their effects through changes in the organization of the cytoskeletal elements across the seminiferous epithelium of adult rat testes. As such, there is an intimate relationship between cell polarity, cell adhesion, and cytoskeletal function in the testis. Herein, we critically evaluate these recent findings based on studies on different animal models. We also suggest some crucial future studies to be performed.
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Yuan, Jia, Jeeyeon Cha, Wenbo Deng, Amanda Bartos, Xiaofei Sun, Hsin-Yi Henry Ho, Jean-Paul Borg, Terry P. Yamaguchi, Yingzi Yang, and Sudhansu K. Dey. "Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation." Proceedings of the National Academy of Sciences 113, no. 50 (November 28, 2016): E8079—E8088. http://dx.doi.org/10.1073/pnas.1614946113.
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Blastocyst implantation is a complex process requiring coordination of a dynamic sequence of embryo–uterine interactions. Blood vessels enter the uterus from the mesometrium, demarcating the uterus into mesometrial (M) and antimesometrial (AM) domains. Implantation occurs along the uterine longitudinal axis within specialized implantation chambers (crypts) that originate within the evaginations directed from the primary lumen toward the AM domain. The morphological orientation of crypts in rodent uteri was recognized more than a century ago, but the mechanism remained unknown. Here we provide evidence that planar cell polarity (PCP) signaling orchestrates directed epithelial evaginations to form crypts for implantation in mice. Uterine deletion of Vang-like protein 2, but not Vang-like protein 1, conferred aberrant PCP signaling, misdirected epithelial evaginations, defective crypt formation, and blastocyst attachment, leading to severely compromised pregnancy outcomes. The study reveals a previously unrecognized role for PCP in executing spatial cues for crypt formation and implantation. Because PCP is an evolutionarily conserved phenomenon, our study is likely to inspire implantation studies of this signaling pathway in humans and other species.
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Kim, Yeon Sun, Yingju Li, Jia Yuan, Jean-Paul Borg, Xiaofei Sun, and Sudhansu K. Dey. "Cannabinoid and planar cell polarity signaling converges to direct placentation." Proceedings of the National Academy of Sciences 118, no. 38 (September 14, 2021): e2108201118. http://dx.doi.org/10.1073/pnas.2108201118.
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Directed trophoblast migration toward the maternal mesometrial pole is critical for placentation and pregnancy success. Trophoblasts replace maternal arterial endothelial cells to increase blood supply to the placenta. Inferior trophoblast invasion results in pregnancy complications including preeclampsia, intrauterine growth restriction, miscarriage, and preterm delivery. The maternal chemotactic factors that direct trophoblast migration and the mechanism by which trophoblasts respond to these factors are not clearly understood. Here, we show that invasive trophoblasts deficient in Vangl2, a core planar cell polarity (PCP) component, fail to invade in maternal decidua, and this deficiency results in middle-gestational fetal demise. Previously, we have shown that tightly regulated endocannabinoids via G protein–coupled cannabinoid receptor CB1 are critical to the invasion of trophoblasts called spiral artery trophoblast giant cells (SpA-TGCs). We find that CB1 directly interacts with VANGL2. Trophoblast stem cells devoid of Cnr1 and/or Vangl2 show compromised cell migration. To study roles of VANGL2 and CB1 in trophoblast invasion in vivo, we conditionally deleted Cnr1 (coding CB1) and Vangl2 in progenitors of SpA-TGCs using trophoblast-specific protein alpha (Tpbpa)-Cre. We observed that signaling mediated by VANGL2 and CB1 restrains trophoblasts from random migration by keeping small GTPases quiescent. Our results show that organized PCP in trophoblasts is indispensable for their directed movement and that CB1 exerts its function by direct interaction with membrane proteins other than its canonical G protein–coupled receptor role.
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Carvajal-Gonzalez, Jose Maria, Sonia Mulero-Navarro, Michael Smith, and Marek Mlodzik. "A Novel Frizzled-Based Screening Tool Identifies Genetic Modifiers of Planar Cell Polarity in Drosophila Wings." G3 Genes|Genomes|Genetics 6, no. 12 (December 1, 2016): 3963–73. http://dx.doi.org/10.1534/g3.116.035535.
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Abstract Most mutant alleles in the Fz-PCP pathway genes were discovered in classic Drosophila screens looking for recessive loss-of-function (LOF) mutations. Nonetheless, although Fz-PCP signaling is sensitive to increased doses of PCP gene products, not many screens have been performed in the wing under genetically engineered Fz overexpression conditions, mostly because the Fz phenotypes were strong and/or not easy to score and quantify. Here, we present a screen based on an unexpected mild Frizzled gain-of-function (GOF) phenotype. The leakiness of a chimeric Frizzled protein designed to be accumulated in the endoplasmic reticulum (ER) generated a reproducible Frizzled GOF phenotype in Drosophila wings. Using this genotype, we first screened a genome-wide collection of large deficiencies and found 16 strongly interacting genomic regions. Next, we narrowed down seven of those regions to finally test 116 candidate genes. We were, thus, able to identify eight new loci with a potential function in the PCP context. We further analyzed and confirmed krasavietz and its interactor short-stop as new genes acting during planar cell polarity establishment with a function related to actin and microtubule dynamics.
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Derish, Ida, Jeremy Lee, Sima Babayeva, and Elena Torban. "Role of Core Planar Cell Polarity Vangl2 Gene in the Renal Tubule Development in Mice." McGill Science Undergraduate Research Journal 13, no. 1 (April 9, 2018): 28–31. http://dx.doi.org/10.26443/msurj.v13i1.30.
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Background: Polycystic kidney disease (PKD) is a common kidney disease that affects the development and maintenance of renal tubules, leads to cyst formation, and often progresses to end-stage kidney disease. It has been postulated that defective planar cell polarity (PCP) signaling contributes to initiation of cyst formation in PKD via controlling both convergent extension (CE, a process of directional cell movements) and oriented cell division (OCD, a process of directional cell divisions during tubular elongation post-natally). Indeed, mutations of the key PCP gene, Van Gogh-like 2 (Vangl2), lead to abnormal renal tubules in murine embryonic kidneys, correlating with the original postulate. Methods: In order to further understand the influence of the Vangl2 gene on renal morphogenesis and cystogenesis, control and Vangl2 mutant embryos—as well as post-natal Vangl2 mice with conditional excision of the Vangl2 gene in renal collecting tubules—were generated, then analyzed using immunostaining and fluorescence microscopy. Results: Our results show that Vangl2 plays a role in CE and apical constriction (AC) during embryonic stage of tubulogenesis. Compared to control animals, mutant Vangl2Δ/Δ and conditional Vangl2Δ/CD embryos displayed: i) a significant dilation in the diameter of renal tubules seen as an increased tubule cross-section area and a larger number of cells per cross-section; and ii) changes in cell shape indicative of defective AC. Surprisingly, post-natal mice showed virtually no difference in any of these aspects comparing to control mice, suggesting that other pathways may compensate for the lack of PCP signaling in maintenance of the tubule architecture. Limitations: a) The analysis of the renal tubules at the specific time points does not account for the dynamics of tubular movement and growth in real time; b) a mechanistic and morphological distinction between mice and humans may exist in the renal collecting duct tubules, pertaining to the Vangl2 gene’s influence in the PCP pathway; and c) the degree of mosaicism resulting from the gene excision by Cre-recombinase may correlate with the severity of the phenotype. Conclusion: We conclude that the PCP pathway is required for normal tubule development during embryogenesis. Our results, however, indicate that the cystogenesis seen in PKD postnatally may not be directly attributed to the disrupted PCP signaling, and requires the derangement of additional pathways.
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Lee, Wei-Hsuan, Edwin Corgiat, J. Christopher Rounds, Zenyth Shepherd, Anita H. Corbett, and Kenneth H. Moberg. "A Genetic Screen Links the Disease-Associated Nab2 RNA-Binding Protein to the Planar Cell Polarity Pathway in Drosophila melanogaster." G3: Genes|Genomes|Genetics 10, no. 10 (August 17, 2020): 3575–83. http://dx.doi.org/10.1534/g3.120.401637.
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Mutations in the gene encoding the ubiquitously expressed RNA-binding protein ZC3H14 result in a non-syndromic form of autosomal recessive intellectual disability in humans. Studies in Drosophila have defined roles for the ZC3H14 ortholog, Nab2 (aka Drosophila Nab2 or dNab2), in axon guidance and memory due in part to interaction with a second RNA-binding protein, the fly Fragile X homolog Fmr1, and coregulation of shared Nab2-Fmr1 target mRNAs. Despite these advances, neurodevelopmental mechanisms that underlie defective axonogenesis in Nab2 mutants remain undefined. Nab2 null phenotypes in the brain mushroom bodies (MBs) resemble defects caused by alleles that disrupt the planar cell polarity (PCP) pathway, which regulates planar orientation of static and motile cells via a non-canonical arm of the Wnt/Wg pathway. A kinked bristle phenotype in surviving Nab2 mutant adults additionally suggests a defect in F-actin polymerization and bundling, a PCP-regulated processes. To test for Nab2-PCP genetic interactions, a collection of PCP mutant alleles was screened for modification of a rough-eye phenotype produced by Nab2 overexpression in the eye (GMR>Nab2) and, subsequently, for modification of a viability defect among Nab2 nulls. Multiple PCP alleles dominantly modify GMR>Nab2 eye roughening and a subset rescue low survival and thoracic bristle kinking in Nab2 zygotic nulls. Collectively, these genetic interactions identify the PCP pathway as a potential target of the Nab2 RNA-binding protein in developing eye and wing tissues and suggest that altered PCP signaling could contribute to neurological defects that result from loss of Drosophila Nab2 or its vertebrate ortholog ZC3H14.
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Beati, Hamze, Irina Peek, Paulina Hordowska, Mona Honemann-Capito, Jade Glashauser, Fabian A. Renschler, Parisa Kakanj, et al. "The adherens junction–associated LIM domain protein Smallish regulates epithelial morphogenesis." Journal of Cell Biology 217, no. 3 (January 22, 2018): 1079–95. http://dx.doi.org/10.1083/jcb.201610098.
Full textAbstract:
In epithelia, cells adhere to each other in a dynamic fashion, allowing the cells to change their shape and move along each other during morphogenesis. The regulation of adhesion occurs at the belt-shaped adherens junction, the zonula adherens (ZA). Formation of the ZA depends on components of the Par–atypical PKC (Par-aPKC) complex of polarity regulators. We have identified the Lin11, Isl-1, Mec-3 (LIM) protein Smallish (Smash), the orthologue of vertebrate LMO7, as a binding partner of Bazooka/Par-3 (Baz), a core component of the Par-aPKC complex. Smash also binds to Canoe/Afadin and the tyrosine kinase Src42A and localizes to the ZA in a planar polarized fashion. Animals lacking Smash show loss of planar cell polarity (PCP) in the embryonic epidermis and reduced cell bond tension, leading to severe defects during embryonic morphogenesis of epithelial tissues and organs. Overexpression of Smash causes apical constriction of epithelial cells. We propose that Smash is a key regulator of morphogenesis coordinating PCP and actomyosin contractility at the ZA.
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Dreyer, Courtney A., Kacey VanderVorst, and Kermit L. Carraway. "Vangl as a Master Scaffold for Wnt/Planar Cell Polarity Signaling in Development and Disease." Frontiers in Cell and Developmental Biology 10 (May 11, 2022). http://dx.doi.org/10.3389/fcell.2022.887100.
Full textAbstract:
The establishment of polarity within tissues and dynamic cellular morphogenetic events are features common to both developing and adult tissues, and breakdown of these programs is associated with diverse human diseases. Wnt/Planar cell polarity (Wnt/PCP) signaling, a branch of non-canonical Wnt signaling, is critical to the establishment and maintenance of polarity in epithelial tissues as well as cell motility events critical to proper embryonic development. In epithelial tissues, Wnt/PCP-mediated planar polarity relies upon the asymmetric distribution of core proteins to establish polarity, but the requirement for this distribution in Wnt/PCP-mediated cell motility remains unclear. However, in both polarized tissues and migratory cells, the Wnt/PCP-specific transmembrane protein Vangl is required and appears to serve as a scaffold upon which the core pathway components as well as positive and negative regulators of Wnt/PCP signaling assemble. The current literature suggests that the multiple interaction domains of Vangl allow for the binding of diverse signaling partners for the establishment of context- and tissue-specific complexes. In this review we discuss the role of Vangl as a master scaffold for Wnt/PCP signaling in epithelial tissue polarity and cellular motility events in developing and adult tissues, and address how these programs are dysregulated in human disease.
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Li, Xiaofei, Daogong Zhang, Lei Xu, Yuechen Han, Wenwen Liu, Wei Li, Zhaomin Fan, et al. "Planar Cell Polarity Defects and Hearing Loss in Sperm-Associated Antigen 6 (Spag6)-Deficient Mice." American Journal of Physiology-Cell Physiology, November 11, 2020. http://dx.doi.org/10.1152/ajpcell.00166.2020.
Full textAbstract:
Spag6 encodes an axoneme central apparatus protein that is required for normal flagellar and cilia motility. Recent findings suggest that Spag6 also plays a role in ciliogenesis, orientation of cilia basal feet, and planar polarity. Sensory cells of the inner ear display unique structural features that underlie their mechanosensitivity. They represent a distinctive form of cellular polarity, known as planar cell polarity (PCP). However, a role for Spag6 in the inner ear has not yet been explored. In the present study, the function of Spag6 in the inner ear was examined using Spag6-deficient mice. Our results demonstrate hearing loss in the Spag6 mutants, associated with abnormalities in cellular patterning, cell shape, stereocilia bundles and basal bodies, as well as abnormally distributed Frizzled class receptor 6 (FZD6), suggesting that Spag6 participates in PCP regulation. Moreover, we found that the sub-apical microtubule meshwork was disrupted. Our observations suggest new functions for Spag6 in hearing and PCP in the inner ear.
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Balaraju, Anurag Kakkerla, Bo Hu, Juan J. Rodriguez, Matthew Murry, and Fang Lin. "Glypican 4 regulates planar cell polarity of endoderm cells by controlling the localization of Cadherin 2." Development 148, no. 14 (July 12, 2021). http://dx.doi.org/10.1242/dev.199421.
Full textAbstract:
ABSTRACT Noncanonical Wnt/planar cell polarity (Wnt/PCP) signaling has been implicated in endoderm morphogenesis. However, the underlying cellular and molecular mechanisms of this process are unclear. We found that, during convergence and extension (C&E) in zebrafish, gut endodermal cells are polarized mediolaterally, with GFP-Vangl2 enriched at the anterior edges. Endoderm cell polarity is lost and intercalation is impaired in the absence of glypican 4 (gpc4), a heparan-sulfate proteoglycan that promotes Wnt/PCP signaling, suggesting that this signaling is required for endodermal cell polarity. Live imaging revealed that endoderm C&E is accomplished by polarized cell protrusions and junction remodeling, which are impaired in gpc4-deficient endodermal cells. Furthermore, in the absence of gpc4, Cadherin 2 expression on the endodermal cell surface is increased as a result of impaired Rab5c-mediated endocytosis, which partially accounts for the endodermal defects in these mutants. These findings indicate that Gpc4 regulates endodermal planar cell polarity during endoderm C&E by influencing the localization of Cadherin 2. Thus, our study uncovers a new mechanism by which Gpc4 regulates planar cell polarity and reveals the role of Wnt/PCP signaling in endoderm morphogenesis.
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Basta, Lena P., Michael Hill-Oliva, Sarah V. Paramore, Rishabh Sharan, Audrey Goh, Abhishek Biswas, Marvin Cortez, Katherine A. Little, Eszter Posfai, and Danelle Devenport. "New mouse models for high resolution and live imaging of planar cell polarity proteins in vivo." Development, August 31, 2021. http://dx.doi.org/10.1242/dev.199695.
Full textAbstract:
The collective polarization of cellular structures and behaviors across a tissue plane is a near universal feature of epithelia known as planar cell polarity (PCP). This property is controlled by the core PCP pathway, which is comprised of highly conserved membrane-associated protein complexes that localize asymmetrically at cell junctions. Here we introduce three new mouse models for investigating the localization and dynamics of transmembrane PCP proteins Celsr1, Fz6, and Vangl2. Using the skin epidermis as a model, we characterize and verify the expression, localization and function of endogenously-tagged Celsr1-3xGFP, Fz6-3xGFP and tdTomato-Vangl2 fusion proteins. Live imaging of Fz6-3xGFP in basal epidermal progenitors reveals that the polarity of the tissue is not fixed through time. Rather asymmetry dynamically shifts during cell rearrangements and divisions, while global, average polarity of the tissue is preserved. We show using super-resolution STED imaging that Fz6-3xGFP and tdTomato-Vangl2 can be resolved, enabling us to observe their complex localization along junctions. We further explore PCP fusion protein localization in the trachea and neural tube, and discover new patterns of PCP expression and localization throughout the mouse embryo.