Deficiency in crumbs homolog 2 (<i>Crb2</i>) affects gastrulation and results in embryonic lethality in mice

Xiao, Zhijie; Patrakka, Jaakko; Nukui, Masatoshi; Chi, Lijun; Niu, Dadi; Betsholtz, Christer; Pikkarainen, Timo; Vainio, Seppo; Tryggvason, Karl

doi:10.1002/dvdy.22778

Cited by 73 publications

(74 citation statements)

References 69 publications

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“…One important player in the EPP is Crumbs (Crb), originally identified in Drosophila. Loss of function of Drosophila crb causes loss of apico-basal polarity and tissue integrity in many embryonic epithelia (Grawe et al, 1996;Jürgens et al, 1984;Tepass, 1996;, and comparable phenotypes are observed in mouse embryos lacking either Crb2 or Crb3, two of the three mammalian Crb genes (Whiteman et al, 2014;Xiao et al, 2011). These results highlight the functional conservation from flies to mammals.…”

Section: Introductionmentioning

confidence: 89%

AP-2-complex-mediated endocytosis of Drosophila Crumbs regulates polarity by antagonizing Stardust

Lin

Currinn

Pocha

et al. 2015

Journal of Cell Science

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Maintenance of epithelial polarity depends on the correct localization and levels of polarity determinants. The evolutionarily conserved transmembrane protein Crumbs is crucial for the size and identity of the apical membrane, yet little is known about the molecular mechanisms controlling the amount of Crumbs at the surface. Here, we show that Crumbs levels on the apical membrane depend on a well-balanced state of endocytosis and stabilization. The adaptor protein 2 (AP-2) complex binds to a motif in the cytoplasmic tail of Crumbs that overlaps with the binding site of Stardust, a protein known to stabilize Crumbs on the surface. Preventing endocytosis by mutation of AP-2 causes expansion of the Crumbspositive plasma membrane domain and polarity defects, which can be partially rescued by removing one copy of crumbs. Strikingly, knocking down both AP-2 and Stardust leads to the retention of Crumbs on the membrane. This study provides evidence for a molecular mechanism, based on stabilization and endocytosis, to adjust surface levels of Crumbs, which are essential for maintaining epithelial polarity.

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Section: Introductionmentioning

confidence: 89%

AP-2-complex-mediated endocytosis of Drosophila Crumbs regulates polarity by antagonizing Stardust

Lin

Currinn

Pocha

et al. 2015

Journal of Cell Science

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“…In Drosophila embryos, loss of crb function results in embryonic lethality, caused by the breakdown of many epithelia (Grawe et al, 1996;Tepass, 1996;. Comparable phenotypes are observed in mouse embryos lacking Crb2 or Crb3, two of the three mammalian Crb genes (Charrier et al, 2015;Szymaniak et al, 2015;Whiteman et al, 2014;Xiao et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Drosophila Crumbs prevents ectopic Notch activation in developing wings by inhibiting ligand-independent endocytosis

Nemetschke

Knust

2016

Development

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Many signalling components are apically restricted in epithelial cells, and receptor localisation and abundance is key for morphogenesis and tissue homeostasis. Hence, controlling apicobasal epithelial polarity is crucial for proper signalling. Notch is a ubiquitously expressed, apically localised receptor, which performs a plethora of functions; therefore, its activity has to be tightly regulated. Here, we show that Drosophila Crumbs, an evolutionarily conserved polarity determinant, prevents Notch endocytosis in developing wings through direct interaction between the two proteins. Notch endocytosis in the absence of Crumbs results in the activation of the ligand-independent, Deltex-dependent Notch signalling pathway, and does not require the ligands Delta and Serrate or γ-secretase activity. This function of Crumbs is not due to general defects in apicobasal polarity, as localisation of other apical proteins is unaffected. Our data reveal a mechanism to explain how Crumbs directly controls localisation and trafficking of the potent Notch receptor, and adds yet another aspect of Crumbs regulation in Notch pathway activity. Furthermore, our data highlight a close link between the apical determinant Crumbs, receptor trafficking and tissue homeostasis.

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“…CRB2 distribution overlaps that of CRB1, but CRB2 is also found in other organs such as kidneys (15). CRB2 is required for retinal integrity and for gastrulation of mouse embryos (16,17). CRB3 is widely expressed in epithelial tissues and exists as two isoforms, namely, CRB3A and CRB3B (18,19).…”

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confidence: 99%

CRB3A Controls the Morphology and Cohesion of Cancer Cells through Ehm2/p114RhoGEF-Dependent Signaling

Loie

Charrier

Sollier

et al. 2015

Molecular and Cellular Biology

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The transmembrane protein CRB3A controls epithelial cell polarization. Elucidating the molecular mechanisms of CRB3A function is essential as this protein prevents the epithelial-to-mesenchymal transition (EMT), which contributes to tumor progression. To investigate the functional impact of altered CRB3A expression in cancer cells, we expressed CRB3A in HeLa cells, which are devoid of endogenous CRB3A. While control HeLa cells display a patchy F-actin distribution, CRB3A-expressing cells form a circumferential actomyosin belt. This reorganization of the cytoskeleton is accompanied by a transition from an ameboid cell shape to an epithelial-cell-like morphology. In addition, CRB3A increases the cohesion of HeLa cells. To perform these functions, CRB3A recruits p114RhoGEF and its activator Ehm2 to the cell periphery using both functional motifs of its cytoplasmic tail and increases RhoA activation levels. ROCK1 and ROCK2 (ROCK1/2), which are critical effectors of RhoA, are also essential to modulate the cytoskeleton and cell shape downstream of CRB3A. Overall, our study highlights novel roles for CRB3A and deciphers the signaling pathway conferring to CRB3A the ability to fulfill these functions. Thereby, our data will facilitate further investigation of CRB3A functions and increase our understanding of the cellular defects associated with the loss of CRB3A expression in cancer cells.T he physiology of epithelial cells relies on the asymmetric distribution of specific cellular constituents-a structural organization referred to as epithelial polarity (1). Epithelial cell polarization results in the regionalization of the plasma membrane into apical, lateral, and basal domains. In vertebrate epithelial cells, the apical and lateral domains are segregated by tight junctions (TJ), which seal the intercellular space to prevent passive diffusion across the tissue (2). Different groups of apical and lateral proteins cooperate within their respective domains to elaborate membrane territories with specific compositions and functions (3). In addition, the mutual antagonism between apical and lateral protein complexes defines a sharp apicolateral boundary (3). Pioneer studies in Drosophila melanogaster have established that one of these protein complexes is articulated around the transmembrane apical protein Crumbs (Crb) (4-7). The mammalian genome encodes three Crb orthologs, namely, CRB1, CRB2, and CRB3 (8). CRB1 is expressed mainly in the brain, cornea, and retina (9, 10). Mutations in the human CRB1 or mouse Crb1 gene cause retinal dystrophies (11)(12)(13)(14). CRB2 distribution overlaps that of CRB1, but CRB2 is also found in other organs such as kidneys (15). CRB2 is required for retinal integrity and for gastrulation of mouse embryos (16, 17). CRB3 is widely expressed in epithelial tissues and exists as two isoforms, namely, CRB3A and CRB3B (18,19). The latter associates with spindle poles during mitosis or is found in the primary cilium of epithelial cells to control cytokinesis and ciliogenesis (19). CRB3A is apical...

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Deficiency in crumbs homolog 2 (Crb2) affects gastrulation and results in embryonic lethality in mice

Cited by 73 publications

References 69 publications

AP-2-complex-mediated endocytosis of Drosophila Crumbs regulates polarity by antagonizing Stardust

AP-2-complex-mediated endocytosis of Drosophila Crumbs regulates polarity by antagonizing Stardust

Drosophila Crumbs prevents ectopic Notch activation in developing wings by inhibiting ligand-independent endocytosis

CRB3A Controls the Morphology and Cohesion of Cancer Cells through Ehm2/p114RhoGEF-Dependent Signaling

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