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1
Ezan, Jérôme, and Mireille Montcouquiol. "Les liens multiples entre les cils et la polarité planaire cellulaire." médecine/sciences 30, no. 11 (November 2014): 1004–10. http://dx.doi.org/10.1051/medsci/20143011015.
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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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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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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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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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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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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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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.
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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.
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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.
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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.
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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.
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Wang, Shixuan, Jinghua Hu, and Zheng Dong. "From Primary Cilia and Planar Cell Polarity to Kidney Injury and Repair." Nephron, July 17, 2023, 1. http://dx.doi.org/10.1159/000531294.
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Almost every cell in the kidney, including renal tubular epithelial cells, has a primary cilium, which is a membrane-bound, hair-like structure protruding from the cellular surface. Dysfunction of primary cilia has been linked to a wide spectrum of human genetic diseases, termed ciliopathies. Planar cell polarity (PCP) refers to the coordinated alignment of cells along the cell sheet or tissue plane, a fundamental process in embryo development and organogenesis. Interestingly, there is evidence that primary cilium and PCP are interconnected. However, very limited is known about the involvement of cilia and PCP in kidney injury and repair. By using cell and mouse models, we have demonstrated a protective role of primary cilia in acute kidney injury. Mechanistically, we unveiled a reciprocal promoting relationship between cilia and autophagy in kidney tubular cells, and, accordingly, cilia may protect tubular cells by enhancing autophagy. Our recent studies further demonstrated that PCP dysfunction exaggerates acute kidney injury and may also contribute to maladaptive kidney repair after acute kidney injury. These findings provide a novel dimension to further understanding kidney injury and repair from the standpoint of cell biology.
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Kim, Sally Yunsun, David McTeague, Sek-Shir Cheong, Matthew Hind, and Charlotte H. Dean. "Deciphering the impacts of modulating the Wnt-planar cell polarity (PCP) pathway on alveolar repair." Frontiers in Cell and Developmental Biology 12 (February 27, 2024). http://dx.doi.org/10.3389/fcell.2024.1349312.
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Many adult lung diseases involve dysregulated lung repair. Deciphering the molecular and cellular mechanisms that govern intrinsic lung repair is essential to develop new treatments to repair/regenerate the lungs. Aberrant Wnt signalling is associated with lung diseases including emphysema, idiopathic pulmonary fibrosis and pulmonary arterial hypertension but how Wnt signalling contributes to these diseases is still unclear. There are several alternative pathways that can be stimulated upon Wnt ligand binding, one of these is the Planar Cell Polarity (PCP) pathway which induces actin cytoskeleton remodelling. Wnt5a is known to stimulate the PCP pathway and this ligand is of particular interest in regenerative lung biology because of its association with lung diseases and its role in the alveolar stem cell niche. To decipher the cellular mechanisms through which Wnt5a and the PCP pathway affect alveolar repair we utilised a 3-D ex-vivo model of lung injury and repair, the AIR model. Our results show that Wnt5a specifically enhances the alveolar epithelial progenitor cell population following injury and surprisingly, this function is attenuated but not abolished in Looptail (Lp) mouse lungs in which the PCP pathway is dysfunctional. However, Lp tracheal epithelial cells show reduced stiffness and Lp alveolar epithelial cells are less migratory than wildtype (WT), indicating that Lp lung epithelial cells have a reduced capacity for repair. These findings provide important mechanistic insight into how Wnt5a and the PCP pathway contribute to lung repair and indicate that these components of Wnt signalling may be viable targets for the development of pro-repair treatments.
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Dominicci-Cotto, Carihann, Mariam Vazquez, and Bruno Marie. "The Wingless planar cell polarity pathway is essential for optimal activity-dependent synaptic plasticity." Frontiers in Synaptic Neuroscience 16 (April 3, 2024). http://dx.doi.org/10.3389/fnsyn.2024.1322771.
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From fly to man, the Wingless (Wg)/Wnt signaling molecule is essential for both the stability and plasticity of the nervous system. The Drosophila neuromuscular junction (NMJ) has proven to be a useful system for deciphering the role of Wg in directing activity-dependent synaptic plasticity (ADSP), which, in the motoneuron, has been shown to be dependent on both the canonical and the noncanonical calcium Wg pathways. Here we show that the noncanonical planar cell polarity (PCP) pathway is an essential component of the Wg signaling system controlling plasticity at the motoneuron synapse. We present evidence that disturbing the PCP pathway leads to a perturbation in ADSP. We first show that a PCP-specific allele of disheveled (dsh) affects the de novo synaptic structures produced during ADSP. We then show that the Rho GTPases downstream of Dsh in the PCP pathway are also involved in regulating the morphological changes that take place after repeated stimulation. Finally, we show that Jun kinase is essential for this phenomenon, whereas we found no indication of the involvement of the transcription factor complex AP1 (Jun/Fos). This work shows the involvement of the neuronal PCP signaling pathway in supporting ADSP. Because we find that AP1 mutants can perform ADSP adequately, we hypothesize that, upon Wg activation, the Rho GTPases and Jun kinase are involved locally at the synapse, in instructing cytoskeletal dynamics responsible for the appearance of the morphological changes occurring during ADSP.
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Stansak, Kendra L., Luke D. Baum, Sumana Ghosh, Punam Thapa, Vineel Vanga, and Bradley J. Walters. "PCP auto count: a novel Fiji/ImageJ plug-in for automated quantification of planar cell polarity and cell counting." Frontiers in Cell and Developmental Biology 12 (May 17, 2024). http://dx.doi.org/10.3389/fcell.2024.1394031.
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Introdution: During development, planes of cells give rise to complex tissues and organs. The proper functioning of these tissues is critically dependent on proper inter- and intra-cellular spatial orientation, a feature known as planar cell polarity (PCP). To study the genetic and environmental factors affecting planar cell polarity, investigators must often manually measure cell orientations, which is a time-consuming endeavor. To automate cell counting and planar cell polarity data collection we developed a Fiji/ImageJ plug-in called PCP Auto Count (PCPA).Methods: PCPA analyzes binary images and identifies “chunks” of white pixels that contain “caves” of infiltrated black pixels. For validation, inner ear sensory epithelia including cochleae and utricles from mice were immunostained for βII-spectrin and imaged with a confocal microscope. Images were preprocessed using existing Fiji functionality to enhance contrast, make binary, and reduce noise. An investigator rated PCPA cochlear hair cell angle measurements for accuracy using a one to five agreement scale. For utricle samples, PCPA derived measurements were directly compared against manually derived angle measurements and the concordance correlation coefficient (CCC) and Bland-Altman limits of agreement were calculated. PCPA was also tested against previously published images examining PCP in various tissues and across various species suggesting fairly broad utility.Results: PCPA was able to recognize and count 99.81% of cochlear hair cells, and was able to obtain ideally accurate planar cell polarity measurements for at least 96% of hair cells. When allowing for a <10° deviation from “perfect” measurements, PCPA’s accuracy increased to 98%–100% for all users and across all samples. When PCPA’s measurements were compared with manual angle measurements for E17.5 utricles there was negligible bias (<0.5°), and a CCC of 0.999. Qualitative examination of example images of Drosophila ommatidia, mouse ependymal cells, and mouse radial progenitors revealed a high level of accuracy for PCPA across a variety of stains, tissue types, and species.Discussion: Altogether, the data suggest that the PCPA plug-in suite is a robust and accurate tool for the automated collection of cell counts and PCP angle measurements.
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Piscitello-Gómez, Romina, Franz S. Gruber, Abhijeet Krishna, Charlie Duclut, Carl D. Modes, Marko Popović, Frank Jülicher, Natalie A. Dye, and Suzanne Eaton. "Core PCP mutations affect short time mechanical properties but not tissue morphogenesis in the Drosophila pupal wing." eLife 12 (December 20, 2023). http://dx.doi.org/10.7554/elife.85581.
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How morphogenetic movements are robustly coordinated in space and time is a fundamental open question in biology. We study this question using the wing of Drosophila melanogaster, an epithelial tissue that undergoes large-scale tissue flows during pupal stages. Previously, we showed that pupal wing morphogenesis involves both cellular behaviors that allow relaxation of mechanical tissue stress, as well as cellular behaviors that appear to be actively patterned (Etournay et al., 2015). Here, we show that these active cellular behaviors are not guided by the core planar cell polarity (PCP) pathway, a conserved signaling system that guides tissue development in many other contexts. We find no significant phenotype on the cellular dynamics underlying pupal morphogenesis in mutants of core PCP. Furthermore, using laser ablation experiments, coupled with a rheological model to describe the dynamics of the response to laser ablation, we conclude that while core PCP mutations affect the fast timescale response to laser ablation they do not significantly affect overall tissue mechanics. In conclusion, our work shows that cellular dynamics and tissue shape changes during Drosophila pupal wing morphogenesis do not require core PCP as an orientational guiding cue.
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Zhang, Kuan, Erica Yao, Chuwen Lin, Yu-Ting Chou, Julia Wong, Jianying Li, Paul J. Wolters, and Pao-Tien Chuang. "A mammalian Wnt5a–Ror2–Vangl2 axis controls the cytoskeleton and confers cellular properties required for alveologenesis." eLife 9 (May 12, 2020). http://dx.doi.org/10.7554/elife.53688.
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Alveolar formation increases the surface area for gas-exchange and is key to the physiological function of the lung. Alveolar epithelial cells, myofibroblasts and endothelial cells undergo coordinated morphogenesis to generate epithelial folds (secondary septa) to form alveoli. A mechanistic understanding of alveologenesis remains incomplete. We found that the planar cell polarity (PCP) pathway is required in alveolar epithelial cells and myofibroblasts for alveologenesis in mammals. Our studies uncovered a Wnt5a–Ror2–Vangl2 cascade that endows cellular properties and novel mechanisms of alveologenesis. This includes PDGF secretion from alveolar type I and type II cells, cell shape changes of type I cells and migration of myofibroblasts. All these cellular properties are conferred by changes in the cytoskeleton and represent a new facet of PCP function. These results extend our current model of PCP signaling from polarizing a field of epithelial cells to conferring new properties at subcellular levels to regulate collective cell behavior.
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Seo, Ji-Seon, Ioannis Mantas, Per Svenningsson, and Paul Greengard. "Ependymal cells-CSF flow regulates stress-induced depression." Molecular Psychiatry, July 7, 2021. http://dx.doi.org/10.1038/s41380-021-01202-1.
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AbstractMajor depressive disorder (MDD) is a severe, common mood disorder. While reduced cerebrospinal fluid (CSF) flow adversely affects brain metabolism and fluid balance in the aging population and during development, only indirect evidence links aberrant CSF circulation with many diseases including neurological, neurodegenerative, and psychiatric disorders, such as anxiety and depression. Here we show a very high concentration of p11 as a key molecular determinant for depression in ependymal cells, which is significantly decreased in patients with MDD, and in two mouse models of depression induced by chronic stress, such as restraint and social isolation. The loss of p11 in ependymal cells causes disoriented ependymal planar cell polarity (PCP), reduced CSF flow, and depression-like and anxiety-like behaviors. p11 intrinsically controls PCP core genes, which mediates CSF flow. Viral expression of p11 in ependymal cells specifically rescues the pathophysiological and behavioral deficits caused by loss of p11. Taken together, our results identify a new role and a key molecular determinant for ependymal cell-driven CSF flow in mood disorders and suggest a novel strategy for development of treatments for stress-associated neurological, neurodegenerative, and psychiatric disorders.
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Bedogni, Francesco, and Robert F. Hevner. "Cell-Type-Specific Gene Expression in Developing Mouse Neocortex: Intermediate Progenitors Implicated in Axon Development." Frontiers in Molecular Neuroscience 14 (July 12, 2021). http://dx.doi.org/10.3389/fnmol.2021.686034.
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Cerebral cortex projection neurons (PNs) are generated from intermediate progenitors (IPs), which are in turn derived from radial glial progenitors (RGPs). To investigate developmental processes in IPs, we profiled IP transcriptomes in embryonic mouse neocortex, using transgenic Tbr2-GFP mice, cell sorting, and microarrays. These data were used in combination with in situ hybridization to ascertain gene sets specific for IPs, RGPs, PNs, interneurons, and other neural and non-neural cell types. RGP-selective transcripts (n = 419) included molecules for Notch receptor signaling, proliferation, neural stem cell identity, apical junctions, necroptosis, hippo pathway, and NF-κB pathway. RGPs also expressed specific genes for critical interactions with meningeal and vascular cells. In contrast, IP-selective genes (n = 136) encoded molecules for activated Delta ligand presentation, epithelial-mesenchymal transition, core planar cell polarity (PCP), axon genesis, and intrinsic excitability. Interestingly, IPs expressed several “dependence receptors” (Unc5d, Dcc, Ntrk3, and Epha4) that induce apoptosis in the absence of ligand, suggesting a competitive mechanism for IPs and new PNs to detect key environmental cues or die. Overall, our results imply a novel role for IPs in the patterning of neuronal polarization, axon differentiation, and intrinsic excitability prior to mitosis. Significantly, IPs highly express Wnt-PCP, netrin, and semaphorin pathway molecules known to regulate axon polarization in other systems. In sum, IPs not only amplify neurogenesis quantitatively, but also molecularly “prime” new PNs for axogenesis, guidance, and excitability.
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Sidik, Alfire, Groves Dixon, Desire M. Buckley, Hannah G. Kirby, Shuge Sun, and Johann K. Eberhart. "Exposure to ethanol leads to midfacial hypoplasia in a zebrafish model of FASD via indirect interactions with the Shh pathway." BMC Biology 19, no. 1 (July 1, 2021). http://dx.doi.org/10.1186/s12915-021-01062-9.
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Abstract Background Gene-environment interactions are likely to underlie most human birth defects. The most common known environmental contributor to birth defects is prenatal alcohol exposure. Fetal alcohol spectrum disorders (FASD) describe the full range of defects that result from prenatal alcohol exposure. Gene-ethanol interactions underlie susceptibility to FASD, but we lack a mechanistic understanding of these interactions. Here, we leverage the genetic tractability of zebrafish to address this problem. Results We first show that vangl2, a member of the Wnt/planar cell polarity (Wnt/PCP) pathway that mediates convergent extension movements, strongly interacts with ethanol during late blastula and early gastrula stages. Embryos mutant or heterozygous for vangl2 are sensitized to ethanol-induced midfacial hypoplasia. We performed single-embryo RNA-seq during early embryonic stages to assess individual variation in the transcriptional response to ethanol and determine the mechanism of the vangl2-ethanol interaction. To identify the pathway(s) that are disrupted by ethanol, we used these global changes in gene expression to identify small molecules that mimic the effects of ethanol via the Library of Integrated Network-based Cellular Signatures (LINCS L1000) dataset. Surprisingly, this dataset predicted that the Sonic Hedgehog (Shh) pathway inhibitor, cyclopamine, would mimic the effects of ethanol, despite ethanol not altering the expression levels of direct targets of Shh signaling. Indeed, we found that ethanol and cyclopamine strongly, but indirectly, interact to disrupt midfacial development. Ethanol also interacts with another Wnt/PCP pathway member, gpc4, and a chemical inhibitor of the Wnt/PCP pathway, blebbistatin, phenocopies the effect of ethanol. By characterizing membrane protrusions, we demonstrate that ethanol synergistically interacts with the loss of vangl2 to disrupt cell polarity required for convergent extension movements. Conclusions Our results show that the midfacial defects in ethanol-exposed vangl2 mutants are likely due to an indirect interaction between ethanol and the Shh pathway. Vangl2 functions as part of a signaling pathway that regulates coordinated cell movements during midfacial development. Ethanol exposure alters the position of a critical source of Shh signaling that separates the developing eye field into bilateral eyes, allowing the expansion of the midface. Collectively, our results shed light on the mechanism by which the most common teratogen can disrupt development.
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Ghosh, Baishakhi, Pratulya Pragadaraju Chengala, Sonya Shah, Daniel Chen, Vaishnavi Karanam, Kai Wilmsen, Bonnie Yeung-Luk, and Venkataramana K. Sidhaye. "Cigarette smoke-induced injury induces distinct sex-specific transcriptional signatures in mice tracheal epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology, August 22, 2023. http://dx.doi.org/10.1152/ajplung.00104.2023.
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The airway epithelial barrier is crucial for defending against respiratory insults and diseases. Disruption of epithelial integrity contributes to respiratory diseases, and sex-specific differences in susceptibility and severity have been observed. However, sex-specific differences in the context of respiratory diseases are often overlooked, especially in murine models. In this study, we investigated the in vitro transcriptomics of male and female murine tracheal epithelial cells (mTECs) in response to chronic cigarette smoke (CS) exposure using an ISO puff regimen. Our findings reveal sex-specific differences in the baseline characteristics of airway epithelial cells. Female mTECs demonstrated stronger barrier function and higher ciliary function compared to males. The barrier function was disrupted in both males and females following chronic CS, but the difference is more significant in females due to their higher baseline. Female mice exhibited transcriptional signatures suggesting dedifferentiation with increased basal cells and markers of cellular senescence. Pathway analysis indicated potential protective roles of planar cell polarity (PCP) in preventing dedifferentiation in male mice exposed to CS. We also observed sex-specific differences in the DNA damage response and antioxidant levels, suggesting distinct mechanisms underlying cellular stress. Understanding these sex-specific mechanisms could facilitate the development of targeted therapeutic strategies for lung diseases associated with environmental insults. Recognizing sex-based differences in disease susceptibility and treatment response can lead to personalized care and improved outcomes. Clinical trials should consider sex as a biological variable to develop effective interventions that address the unique differences between men and women in respiratory diseases.
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Toubat, Omar, Naikhoba C. Munabi, David W. Craig, William Magee, and Ram Kumar Subramanyan. "Abstract 11001: Wnt/Planar Cell Polarity Pathway Mutations Are Over-Represented in Children with Concomitant Congenital Cardiac and Cleft Malformations." Circulation 144, Suppl_1 (November 16, 2021). http://dx.doi.org/10.1161/circ.144.suppl_1.11001.
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Introduction: We have demonstrated a high association between cleft lip and/or palate (CL/P) and outflow tract congenital heart disease (CHD) in the pediatric population. Despite this strong phenotypic association, the molecular genetics underlying these concomitant disease processes remains unclear. Hypothesis: Genomic profiling of concomitant outflow tract CHD+CL/P patients will unravel mutations in signaling pathways with overlapping importance in heart and palatal development. Methods: Patients with outflow tract CHD+CL/P and no previously known genetic syndromes or positive chromosomal microarrays at our institution between January 2004 and December 2018 were identified. Whole exome sequencing was performed on blood specimens collected from patients and phenotypically normal parents. Gene ontology and pathway analysis of de novo variants identified in probands was performed using PANTHER and DAVID databases and reinforced with a primary literature search. Functional assessment of non-canonical Wnt signaling variants was performed through siRNA-knockdown and wound-healing assays in murine myoblasts. Results: De novo loss-of-function mutations were observed in all 17 probands, in a total of 28 genes. Five genes (18%) have previously been implicated in both heart and palate development (CHD7, MED12, NDST1, GRHL2, SMARCA4). Three genes (11%) were mutated in more than one proband (CHD7, CELSR3, SAPCD2). Gene ontology and pathway analysis of deleterious de novo variants predicted involvement in binding (n=11, 39%), gene-specific transcription (n=9, 32%), and molecular and transcriptional function (n=8, 29%). The Wnt pathway (n=14, 50%) was the most strongly enriched signaling pathway, mutated in 10 (59%) probands, followed by Semaphorin and Endothelin signaling (n=2 variants, 7.1%, each). Knockdown of Wnt/PCP genes SAPCD2, CELSR3, and CCDC88C disrupted myoblast cellular migration in vitro, validating the functionality of these gene candidates. Conclusion: Our study is the first to characterize the genomic profile of patients with concomitant outflow tract CHD+CL/P. Excess de novo mutations in genes involved in Wnt pathway signaling suggests that this pathway plays a crucial role in CHD+CL/P disease pathogenesis.