Planar Cell Polarity Signaling Pathway in Congenital Heart Diseases

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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SHROOM3 is a novel component of the planar cell polarity pathway whose disruption causes congenital heart disease

Proceedings of IMPRS ◽

10.18060/23577 ◽

2019 ◽

Vol 2 (1) ◽

Author(s):

Alison Schmidt ◽

Matthew Durbin, MS MD ◽

James O’Kane, MS ◽

Stephanie M. Ware, MD PHD

Keyword(s):

Congenital Heart Disease ◽

Heart Disease ◽

Signaling Pathway ◽

Cell Polarity ◽

Congenital Heart ◽

Planar Cell Polarity ◽

Cardiac Development ◽

Genetic Interaction ◽

Compound Heterozygous ◽

Pcp Signaling

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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Faculty Opinions recommendation of Mitotic internalization of planar cell polarity proteins preserves tissue polarity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.12441956.14866206 ◽

2012 ◽

Author(s):

Crislyn D'Souza-Schorey

Keyword(s):

Cell Polarity ◽

Planar Cell Polarity ◽

Tissue Polarity ◽

Polarity Proteins

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Faculty Opinions recommendation of Mitotic internalization of planar cell polarity proteins preserves tissue polarity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.12441956.14313061 ◽

2011 ◽

Author(s):

Jonathan Jones

Keyword(s):

Cell Polarity ◽

Planar Cell Polarity ◽

Tissue Polarity ◽

Polarity Proteins

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Coupling Planar Cell Polarity Signaling to Morphogenesis

The Scientific World JOURNAL ◽

10.1100/tsw.2002.105 ◽

2002 ◽

Vol 2 ◽

pp. 434-454 ◽

Cited By ~ 35

Author(s):

Jeffrey D. Axelrod ◽

Helen McNeill

Keyword(s):

Cell Polarity ◽

Planar Cell Polarity ◽

Fruit Fly ◽

Convergent Extension ◽

Cytoskeletal Reorganization ◽

Directional Information ◽

Cochlear Hair Cell ◽

Cellular Asymmetry ◽

Pcp Signaling ◽

Unknown Signal

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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Celsr1 and CAMSAP3 differently regulate intercellular and intracellular cilia orientation in oviduct multiciliated cells

10.1101/2020.08.28.273169 ◽

2020 ◽

Author(s):

Fumiko Matsukawa Usami ◽

Masaki Arata ◽

Dongbo Shi ◽

Sanae Oka ◽

Yoko Higuchi ◽

...

Keyword(s):

Cell Polarity ◽

Planar Cell Polarity ◽

Molecular Mechanisms ◽

The Other ◽

Basal Bodies ◽

Generating Functional ◽

Tissue Polarity ◽

Other Hand ◽

Multiciliated Cells ◽

Polarity Regulation

SummaryThe molecular mechanisms by which cilia orientation is coordinated within and between multiciliated cells (MCCs) is not fully understood. By observing the orientation of basal bodies (BB) in MCCs of mouse oviducts, here, we show that Celsr1, a planar cell polarity (PCP) factor involved in tissue polarity regulation, is dispensable for determining BB orientation in individual cells, whereas CAMSAP3, a microtubule minus-end regulator, is critical for this process but not for PCP. MCCs exhibit a characteristic BB orientation and microtubule gradient along the tissue axis, and these intracellular polarities were maintained in the cells lacking Celsr1, although the intercellular coordination of the polarities was partly disrupted. On the other hand, CAMSAP3 regulated the assembly of microtubules interconnecting BBs by localizing at the BBs, and its mutation led to disruption of intracellular coordination of BB orientation, but not affecting PCP factor localization. Thus, both Celsr1 and CAMSAP3 are responsible for BB orientation but in distinct ways; and therefore, their cooperation should be critical for generating functional multiciliated tissues.

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Planar Cell Polarity Acts Through Septins to Control Collective Cell Movement and Ciliogenesis

Science ◽

10.1126/science.1191184 ◽

2010 ◽

Vol 329 (5997) ◽

pp. 1337-1340 ◽

Cited By ~ 227

Author(s):

Su Kyoung Kim ◽

Asako Shindo ◽

Tae Joo Park ◽

Edwin C. Oh ◽

Srimoyee Ghosh ◽

...

Keyword(s):

Cell Polarity ◽

Planar Cell Polarity ◽

Control Point ◽

Cell Movement ◽

Cytoskeletal Proteins ◽

Pcp Signaling ◽

Cellular Machinery ◽

And Migration ◽

Controlling Behaviors ◽

Shed Light

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

Developmental Cell ◽

10.1016/j.devcel.2010.06.008 ◽

2010 ◽

Vol 19 (1) ◽

pp. 138-147 ◽

Cited By ~ 119

Author(s):

Jacinta Caddy ◽

Tomasz Wilanowski ◽

Charbel Darido ◽

Sebastian Dworkin ◽

Stephen B. Ting ◽

...

Keyword(s):

Signaling Pathway ◽

Cell Polarity ◽

Wound Repair ◽

Planar Cell Polarity

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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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