Non-canonical Wnt signaling regulates cell polarity in female reproductive tract development via van gogh-like 2

vandenBerg, Alysia L.; Sassoon, David

doi:10.1242/dev.034066

Cited by 67 publications

(67 citation statements)

References 74 publications

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“…Therefore, further analyses, such as those using conditional Vangl2 inactivation, are needed in order to establish whether the multilevel polarities observed in the mouse oviduct depend on Vangl2. In addition, in spite of the uterine epithelial abnormalities reported in Vangl2 Lpt/+ (Vandenberg and Sassoon, 2009), the polarized localization of Celsr1, the ciliary motion polarity and the epithelial fold polarity in adult Vangl2…”

Section: Discussionmentioning

confidence: 91%

“…Lpt (Vandenberg and Sassoon, 2009 Lpt/+ adult females show an enlarged and fluid-filled uterus. Although enlarged and fluid-filled uteri were also observed in Celsr1 mutants (data not shown), the postnatal oviduct development could not be analyzed in Vangl2 Lpt/Lpt mice because of perinatal lethality resulting from neural tube closure defects (Copp et al, 1994;Strong and Hollander, 1949).…”

Section: Discussionmentioning

confidence: 99%

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Celsr1 is required for the generation of polarity at multiple levels of the mouse oviduct

et al. 2014

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The oviduct is an important organ in reproduction where fertilization occurs, and through which the fertilized eggs are carried to the uterus in mammals. This organ is highly polarized, where the epithelium forms longitudinal folds along the ovary-uterus axis, and the epithelial multicilia beat towards the uterus to transport the ovulated ova. Here, we analyzed the postnatal development of mouse oviduct and report that multilevel polarities of the oviduct are regulated by a planar cell polarity (PCP) gene, Celsr1. In the epithelium, Celsr1 is concentrated in the specific cellular boundaries perpendicular to the ovary-uterus axis from postnatal day 2. We found a new feature of cellular polarity in the oviduct -the apical surface of epithelial cells is elongated along the ovary-uterus axis. In Celsr1-deficient mice, the ciliary motion is not orchestrated along the ovary-uterus axis and the transport ability of beating cilia is impaired. Epithelial cells show less elongation and randomized orientation, and epithelial folds show randomized directionality and ectopic branches in the mutant. Our mosaic analysis suggests that the geometry of epithelial cells is primarily regulated by Celsr1 and as a consequence the epithelial folds are aligned. Taken together, we reveal the characteristics of the multilevel polarity formation processes in the mouse oviduct epithelium and suggest a novel function of the PCP pathway for proper tissue morphogenesis.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Celsr1 is required for the generation of polarity at multiple levels of the mouse oviduct

et al. 2014

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“…Vertebrate Vangl1/2 protein products are homologues of the Drosophila Strabismus/Van Gogh gene, and consist of two transmembrane domains and a PDZbinding domain. Vangl2 is essential for the kidney [24], prostate and genital development (our unpublished data), and patterning of the female genital tract [25].…”

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confidence: 83%

Planar Polarity Factors as Potential Tumor Suppressors in the Urogenital Tract

2014

J Androl Gynaecol

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Planar Polarity Factors as Potential Tumor Suppressors in the Urogenital Tractby preventing their nuclear entry and induction of the cyclin E and anti-apoptotic proteins. In the absence of a Hippo signal, YAP and TAZ translocate to the nucleus and form transcriptional complexes with a number of factors, including beta-catenin, to promote cell division, survival, and migratory and invasive cell properties.Loss of FAT function contributes to many types of tumors, including the oral, breast, lung, pancreatic and gastric cancers, melanomas and hepatocellular carcinomas [7]. High levels of YAP1 protein correlate with cancer progression, and poor prognosis for the bladder, prostate, ovarian and uterine cancer patients [8][9][10][11][12]. In turn, irradiation induced apoptosis of prostate cancer cells has been linked to a decrease in the levels of the YAP1 protein and a consequent raise in the BAX cell death factor [12]. Both YAP and TAZ proteins have been implicated in cancer cell migration and metastasis [8,13,14]. The known antagonists of the Hippo pathway include the ciliaassociated protein NPHP4 [15] and the integrin-associated kinase, which mediate inhibition of Lats kinases upstream of the YAP/TAZ phosphorylation. The Lats 1/2 expression levels are downregulated in many advanced and metastatic cancers, including in prostate cancer, and this effect has been linked to cancer cell resistance to the attachment-dependent apoptosis [16].The core PCP pathway can be activated by most Wnt ligands, but has a preference for Wnt5a, Wnt9 and Wnt11, which have been designated as "non-canonical" Wnts. Although the Ft/Ds system is considered as the long distance PCP component, the core PCP pathway also has long distance capabilities, enabled by the diffusion of the Wnt ligands [17]. Formation of the Wnt/Fzd complexes is the first step in both the core PCP and Wnt/beta-catenin pathways. Thus, the former is often referred to as the "non-canonical Wnt" signaling. Assembly of the Fzd and Vangl receptor complexes on the apical cell surface appears to favor the PCP pathway [18]. In contrast to the canonical Wnt signaling, the core PCP pathway does not affect nuclear localization of beta-catenin. Furthermore, the core PCP signaling routinely antagonizes the canonical Wnt pathway, first, by recruiting Dvl to the membrane Vangl2 complexes, and also by sequestering other shared components (Wnts, Fzd and Frodo) and promoting the degradation of beta-catenin [19]. The canonical Wnt/beta-catenin signaling is often upregulated in cancers. Therefore, part of the PCP tumor suppressor role is likely exercised simply by suppressing the canonical Wnt targets, while another part is associated with its role in the maintenance of tissue polarity and cohesion.

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“…S1). We chose to use conditional uterine deletion of Vangl2, because looptail mice homozygous for Vangl2 mutation have structural defects in the uterus, with imbibition of fluid into the lumen and defects in the vaginal opening, precluding studies of PCP on implantation (29). In contrast, mice with conditional uterine deletion of Vangl2 (Vangl2 (Fig.…”

Section: Uterine Vangl2 Deletion Causes Defects In Epithelial Evaginamentioning

confidence: 99%

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

Yuan

Cha

Deng

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Blastocyst implantation is a complex process requiring coordination of a dynamic sequence of embryo-uterine interactions. Blood vessels enter the uterus from the mesometrium, demarcating the uterus into mesometrial (M) and antimesometrial (AM) domains. Implantation occurs along the uterine longitudinal axis within specialized implantation chambers (crypts) that originate within the evaginations directed from the primary lumen toward the AM domain. The morphological orientation of crypts in rodent uteri was recognized more than a century ago, but the mechanism remained unknown. Here we provide evidence that planar cell polarity (PCP) signaling orchestrates directed epithelial evaginations to form crypts for implantation in mice. Uterine deletion of Vang-like protein 2, but not Vang-like protein 1, conferred aberrant PCP signaling, misdirected epithelial evaginations, defective crypt formation, and blastocyst attachment, leading to severely compromised pregnancy outcomes. The study reveals a previously unrecognized role for PCP in executing spatial cues for crypt formation and implantation. Because PCP is an evolutionarily conserved phenomenon, our study is likely to inspire implantation studies of this signaling pathway in humans and other species.ffective reciprocal cross-talk between the receptive uterus and a competent blastocyst is critical for successful implantation (1). In nearly all mammals studied, the uterus differentiates into a receptive state timed appropriately with the migration of blastocysts into the uterus to initiate bidirectional communication for implantation. The receptive state is transient; in mice the uterus becomes receptive on day 4 of pregnancy (day 1 = vaginal plug) and refractory to implantation by the afternoon of day 5 (2). The coordinated actions of progesterone and estrogen regulate the proliferation and/or differentiation of major uterine cell types in a spatiotemporal manner to establish this brief window of receptivity for implantation. These changes involve an interplay of ovarian hormones, transcription factors, growth factors, morphogens, cytokines, and other signaling molecules. Aberrations or defects in any of these pathways may result in implantation failure or defective implantation, which propagates adverse ripple effects through the remaining course of gestation, compromising pregnancy outcomes (2-5).Blood vessels enter the uterus from the mesometrium and delineate the uterus into mesometrial (M) and antimesometrial (AM) domains. In mice, blastocyst attachment occurs within specialized crypts (implantation chambers), which originate as epithelial evaginations from the main lumen at orderly spaced intervals at the AM domain. The formation of these directed evaginations is initiated on the morning of day 3, and they elongate by the afternoon of day 4 for blastocyst attachment and subsequent crypt formation in the evening along the Wnt5a gradient (6). Blastocyst attachment coincides with increased endometrial vascular permeability at the site of the attachment, which can...

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Non-canonical Wnt signaling regulates cell polarity in female reproductive tract development via van gogh-like 2

Cited by 67 publications

References 74 publications

Celsr1 is required for the generation of polarity at multiple levels of the mouse oviduct

Celsr1 is required for the generation of polarity at multiple levels of the mouse oviduct

Planar Polarity Factors as Potential Tumor Suppressors in the Urogenital Tract

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

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