Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation

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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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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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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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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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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Par3 is essential for the establishment of planar cell polarity of inner ear hair cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1816333116 ◽

2019 ◽

Vol 116 (11) ◽

pp. 4999-5008 ◽

Cited By ~ 11

Author(s):

Andre Landin Malt ◽

Zachary Dailey ◽

Julia Holbrook-Rasmussen ◽

Yuqiong Zheng ◽

Arielle Hogan ◽

...

Keyword(s):

Hair Cell ◽

Inner Ear ◽

Cell Polarity ◽

Hair Cells ◽

Planar Cell Polarity ◽

Tissue Level ◽

Hair Bundle ◽

Nucleotide Exchange ◽

Genetic Mosaic ◽

Pcp Signaling

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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Nemo-like kinase 1 (Nlk1) and paraxial protocadherin (PAPC) cooperatively control Xenopus gastrulation through regulation of Wnt/planar cell polarity (PCP) signaling

Differentiation ◽

10.1016/j.diff.2016.10.002 ◽

2017 ◽

Vol 93 ◽

pp. 27-38 ◽

Cited By ~ 2

Author(s):

Rahul Kumar ◽

Anja Ciprianidis ◽

Susanne Theiß ◽

Herbert Steinbeißer ◽

Lilian T. Kaufmann

Keyword(s):

Cell Polarity ◽

Planar Cell Polarity ◽

Pcp Signaling

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STAT3 noncell-autonomously controls planar cell polarity during zebrafish convergence and extension

The Journal of Cell Biology ◽

10.1083/jcb.200403110 ◽

2004 ◽

Vol 166 (7) ◽

pp. 975-981 ◽

Cited By ~ 43

Author(s):

Chiemi Miyagi ◽

Susumu Yamashita ◽

Yusuke Ohba ◽

Hisayoshi Yoshizaki ◽

Michiyuki Matsuda ◽

...

Keyword(s):

Cell Polarity ◽

Planar Cell Polarity ◽

Cell Polarization ◽

Rhoa Activity ◽

Stat3 Signaling ◽

Convergence And Extension ◽

Pcp Signaling ◽

Autonomous Activity ◽

Rhoa Signaling ◽

Transcription 3

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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Mutations associated with human neural tube defects display disrupted planar cell polarity in Drosophila

eLife ◽

10.7554/elife.53532 ◽

2020 ◽

Vol 9 ◽

Author(s):

Ashley C Humphries ◽

Sonali Narang ◽

Marek Mlodzik

Keyword(s):

Cell Polarity ◽

Neural Tube ◽

Neural Tube Defects ◽

Developmental Disorders ◽

Planar Cell Polarity ◽

Causative Factor ◽

Limited Data ◽

Post Translational Modification ◽

Pcp Signaling

Planar cell polarity (PCP) and neural tube defects (NTDs) are linked, with a subset of NTD patients found to harbor mutations in PCP genes, but there is limited data on whether these mutations disrupt PCP signaling in vivo. The core PCP gene Van Gogh (Vang), Vangl1/2 in mammals, is the most specific for PCP. We thus addressed potential causality of NTD-associated Vangl1/2 mutations, from either mouse or human patients, in Drosophila allowing intricate analysis of the PCP pathway. Introducing the respective mammalian mutations into Drosophila Vang revealed defective phenotypic and functional behaviors, with changes to Vang localization, post-translational modification, and mechanistic function, such as its ability to interact with PCP effectors. Our findings provide mechanistic insight into how different mammalian mutations contribute to developmental disorders and strengthen the link between PCP and NTD. Importantly, analyses of the human mutations revealed that each is a causative factor for the associated NTD.

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Wnt/PCP controls spreading of Wnt/β-catenin signals by cytonemes in vertebrates

eLife ◽

10.7554/elife.36953 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 38

Author(s):

Benjamin Mattes ◽

Yonglong Dang ◽

Gediminas Greicius ◽

Lilian Tamara Kaufmann ◽

Benedikt Prunsche ◽

...

Keyword(s):

Cell Polarity ◽

Gene Transcription ◽

Receptor Tyrosine Kinase ◽

Planar Cell Polarity ◽

Human Cancer ◽

Autocrine Signaling ◽

Membrane Structures ◽

Intestinal Crypt ◽

Pcp Signaling ◽

Signal Activation

Signaling filopodia, termed cytonemes, are dynamic actin-based membrane structures that regulate the exchange of signaling molecules and their receptors within tissues. However, how cytoneme formation is regulated remains unclear. Here, we show that Wnt/planar cell polarity (PCP) autocrine signaling controls the emergence of cytonemes, and that cytonemes subsequently control paracrine Wnt/β-catenin signal activation. Upon binding of the Wnt family member Wnt8a, the receptor tyrosine kinase Ror2 becomes activated. Ror2/PCP signaling leads to the induction of cytonemes, which mediate the transport of Wnt8a to neighboring cells. In the Wnt-receiving cells, Wnt8a on cytonemes triggers Wnt/β-catenin-dependent gene transcription and proliferation. We show that cytoneme-based Wnt transport operates in diverse processes, including zebrafish development, murine intestinal crypt and human cancer organoids, demonstrating that Wnt transport by cytonemes and its control via the Ror2 pathway is highly conserved in vertebrates.

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Microtubules provide directional information for core PCP function

eLife ◽

10.7554/elife.02893 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 72

Author(s):

Maja Matis ◽

David A Russler-Germain ◽

Qie Hu ◽

Claire J Tomlin ◽

Jeffrey D Axelrod

Keyword(s):

Mathematical Simulation ◽

Cell Polarity ◽

Planar Cell Polarity ◽

Global Alignment ◽

Directional Information ◽

The Core ◽

Initial Polarization ◽

Core Module ◽

Pcp Signaling ◽

Apical Junctions

Planar cell polarity (PCP) signaling controls the polarization of cells within the plane of an epithelium. Two molecular modules composed of Fat(Ft)/Dachsous(Ds)/Four-jointed(Fj) and a ‘PCP-core’ including Frizzled(Fz) and Dishevelled(Dsh) contribute to polarization of individual cells. How polarity is globally coordinated with tissue axes is unresolved. Consistent with previous results, we find that the Ft/Ds/Fj-module has an effect on a MT-cytoskeleton. Here, we provide evidence for the model that the Ft/Ds/Fj-module provides directional information to the core-module through this MT organizing function. We show Ft/Ds/Fj-dependent initial polarization of the apical MT-cytoskeleton prior to global alignment of the core-module, reveal that the anchoring of apical non-centrosomal MTs at apical junctions is polarized, observe that directional trafficking of vesicles containing Dsh depends on Ft, and demonstrate the feasibility of this model by mathematical simulation. Together, these results support the hypothesis that Ft/Ds/Fj provides a signal to orient core PCP function via MT polarization.

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