Epidermal Wound Repair Is Regulated by the Planar Cell Polarity Signaling Pathway

Congenital heart disease (CHD) is the most common cause of death due to birth defects. Despite CHD frequency, the etiology remains mostly unknown. Understanding CHD genetics and elucidating disease mechanism will help establish prognosis, identify comorbidity risks, and develop targeted therapies. CHD often results from disrupted cytoarchitecture and signaling pathways. We have identified a novel CHD candidate SHROOM3, a protein associated with the actin cytoskeleton and the Wnt/Planar Cell Polarity (PCP) signaling pathway. SHROOM3 induces actomyosin constriction within the apical side of cells and is implicated in neural tube defects and chronic renal failure in humans. A recent study demonstrated that SHROOM3 interacts with Dishevelled2 (DVL2), a component of the PCP signaling pathway, suggesting that SHROOM3 serves as an important link between acto-myosin constriction and PCP signaling. PCP signaling establishes cell polarity required for multiple developmental processes, and is required for cardiac development. In Preliminary data we utilized a Shroom3 gene-trap mouse (Shroom3gt/gt) to demonstrated that SHROOM3 disruption leads to cardiac defects phenocopy PCP disruption. We also demonstrate that patients with CHD phenotypes have rare and potentially damaging SHROOM3 variants within SHROOM3’s PCP-binding domain. We hypothesize SHROOM3 is a novel terminal effector of PCP signaling, and disruption is a novel contributor to CHD. To test this, we assessed genetic interaction between SHROOM3 and PCP during cardiac development and the ultimate effect on cell structure and movement. Heterozygous Shroom3+/gt mice and heterozygous Dvl2 +/- mice are phenotypically normal. We demonstrated genetic interaction between SHROOM3 and PCP signaling by generating compound heterozygous Shroom3+/gt ;Dvl2 +/- mice and identifying a Double Outlet Right Ventricle and Ventricular Septal Defect in one embryo. We also observed fewer compound heterozygous mice than anticipated by Mendelian rations (observed: 18.4%; expected: 25%; n=76), suggesting potential lethality in utero. Immunohistochemistry demonstrates disrupted actomyosin in the SHROOM3gt/gt mice, characteristic of PCP disruption. These data help strengthen SHROOM3 as a novel CHD candidate gene and a component of the PCP Signaling pathway. Further characterization of this gene is important for CHD diagnosis and therapeutic development.

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Planar Cell Polarity Signaling Pathway in Congenital Heart Diseases

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/589414 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

Gang Wu ◽

Jiao Ge ◽

Xupei Huang ◽

Yimin Hua ◽

Dezhi Mu

Keyword(s):

Signaling Pathway ◽

Cell Polarity ◽

Congenital Heart ◽

Planar Cell Polarity ◽

Heart Diseases ◽

Multiple Roles ◽

Cardiac Differentiation ◽

Tissue Polarity ◽

Cardiac Disorder ◽

Pcp Signaling

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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The dorsal blastopore lip is a source of signals inducing PCP in the Xenopus neural plate

Biology Open ◽

10.1242/bio.058761 ◽

2021 ◽

Author(s):

Pamela Mancini ◽

Olga Ossipova ◽

Sergei Y. Sokol

Keyword(s):

Signaling Pathway ◽

Cell Polarity ◽

Long Range ◽

Planar Cell Polarity ◽

Critical Role ◽

Neural Plate ◽

Posterior Region ◽

Embryo Tissue ◽

Challenging Question ◽

Egg Polarity

Coordinated polarization of cells in the tissue plane, known as planar cell polarity (PCP), is associated with a signaling pathway critical for the control of morphogenetic processes. Although the segregation of PCP components to opposite cell borders is believed to play a critical role in this pathway, whether PCP derives from egg polarity or preexistent long-range gradient, or forms in response to a localized cue remains a challenging question. Here we investigate the Xenopus neural plate, a tissue that has been previously shown to exhibit PCP. By imaging Vangl2 and Prickle3, we show that PCP is progressively acquired in the neural plate and requires a signal from the posterior region of the embryo. Tissue transplantations indicated that PCP is triggered in the neural plate by a planar cue from the dorsal blastopore lip. The PCP cue did not depend on the orientation of the graft and was distinct from neural inducers. These observations suggest that neuroectodermal PCP is not instructed by a preexisting molecular gradient, but induced by a signal from the dorsal blastopore lip.

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The Frizzled Planar Cell Polarity signaling pathway controls Drosophila wing topography

Developmental Biology ◽

10.1016/j.ydbio.2008.02.041 ◽

2008 ◽

Vol 317 (1) ◽

pp. 354-367 ◽

Cited By ~ 25

Author(s):

Kristy Doyle ◽

Justin Hogan ◽

Meagan Lester ◽

Simon Collier

Keyword(s):

Signaling Pathway ◽

Cell Polarity ◽

Planar Cell Polarity ◽

Drosophila Wing

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The Wnt/Planar Cell Polarity Signaling Pathway Contributes to the Integrity of Tight Junctions in Brain Endothelial Cells

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2013.213 ◽

2013 ◽

Vol 34 (3) ◽

pp. 433-440 ◽

Cited By ~ 37

Author(s):

Cédric Artus ◽

Fabienne Glacial ◽

Kayathiri Ganeshamoorthy ◽

Nicole Ziegler ◽

Maeva Godet ◽

...

Keyword(s):

Endothelial Cells ◽

Signaling Pathway ◽

Tight Junctions ◽

Cell Polarity ◽

Planar Cell Polarity ◽

Osmotic Shock ◽

Brain Endothelial Cells ◽

Wnt Proteins ◽

Mouse Brain Endothelial Cells ◽

Canonical Wnt

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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Planar Cell Polarity and E-Cadherin in Tissue-Scale Shape Changes in Drosophila Embryos

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.619958 ◽

2020 ◽

Vol 8 ◽

Author(s):

Deqing Kong ◽

Jörg Großhans

Keyword(s):

Cell Polarity ◽

Wound Repair ◽

Large Scale ◽

Planar Cell Polarity ◽

Cell Communication ◽

Cell Dynamics ◽

Axis Elongation ◽

Shape Changes ◽

Drosophila Embryos ◽

E Cadherin

Planar cell polarity and anisotropic cell behavior play critical roles in large-scale epithelial morphogenesis, homeostasis, wound repair, and regeneration. Cell–Cell communication and mechano-transduction in the second to minute scale mediated by E-cadherin complexes play a central role in the coordination and self-organization of cellular activities, such as junction dynamics, cell shape changes, and cell rearrangement. Here we review the current understanding in the interplay of cell polarity and cell dynamics during body axis elongation and dorsal closure in Drosophila embryos with a focus on E-cadherin dynamics in linking cell and tissue polarization and tissue-scale shape changes.

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