Dlg1 controls planar spindle orientation in the neuroepithelium through direct interaction with LGN

Saadaoui, Mehdi; Machicoane, Mickaël; Pietro, Florencia di; Etoc, Fred; Échard, Arnaud; Morin, Xavier

doi:10.1083/jcb.201405060

Cited by 64 publications

(106 citation statements)

References 42 publications

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“…This function of nTSG proteins coordinates the geometry of chromosome segregation with the architecture of polarized cell-cell junctions, thereby ensuring epithelial integrity [32]. In vertebrates, Dlg1 has been shown to be localized at the basolateral cell cortex during mitosis, and is necessary for planar spindle orientation in chick neuroepithelium and in human HeLa cells [35]. Conditional deletion of Scrib in mice mammary gland results in excess growth of atypical luminal cells, and development of ductal and alveolar hyperplasia associated with aberrant spindle orientation [36].…”

Section: Spindle Misorientation Basal Delamination and Apoptosis Ofmentioning

confidence: 99%

Tissue-Intrinsic Tumor Hotspots: Terroir for Tumorigenesis

Tamori

Deng

2017

Trends in Cancer

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Epithelial tissues are highly organized systems with a remarkable homeostatic ability to maintain morphology through regulation of cellular proliferation and tissue integrity. This robust self-organizing system is progressively disrupted during tumor development. Recent studies of conserved tumor-suppressor genes in Drosophila showed how pro-tumor cells deviate from the robustly organized tissue microenvironment to take the first steps into becoming aggressive tumors. Here we review the ‘tumor hotspot’ hypothesis that explains how the tissue-intrinsic local microenvironment has a pivotal role in the initial stage of tumorigenesis in Drosophila epithelia and discuss comparable mechanisms in mammalian tissues.

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Section: Spindle Misorientation Basal Delamination and Apoptosis Ofmentioning

confidence: 99%

Tissue-Intrinsic Tumor Hotspots: Terroir for Tumorigenesis

Tamori

Deng

2017

Trends in Cancer

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“…2i). Dlg1 has been implicated in planar spindle orientation through its function in recruiting the LGN complex to the cell cortex 14 , but this function was unperturbed in Pten ΔTKV/ΔTKV MEFs (Supplementary Fig. 2h).…”

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confidence: 99%

Pten regulates spindle pole movement through Dlg1-mediated recruitment of Eg5 to centrosomes

et al. 2016

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Phosphatase and tensin homologue (Pten) suppresses neoplastic growth by negatively regulating PI(3)K signalling through its phosphatase activity1. To gain insight into the actions of non-catalytic Pten domains in normal physiological processes and tumorigenesis2,3, we engineered mice lacking the PDZ-binding domain (PDZ-BD). Here, we show that the PDZ-BD regulates centrosome movement and that its heterozygous or homozygous deletion promotes aneuploidy and tumour formation. We found that Pten is recruited to pre-mitotic centrosomes in a Plk1-dependent fashion to create a docking site for protein complexes containing the PDZ-domain-containing protein Dlg1 (also known as Sap97) and Eg5 (also known as Kif11), a kinesin essential for centrosome movement and bipolar spindle formation4. Docking of Dlg1–Eg5 complexes to Pten depended on Eg5 phosphorylation by the Nek9–Nek6 mitotic kinase cascade and Cdk1. PDZ-BD deletion or Dlg1 ablation impaired loading of Eg5 onto centrosomes and spindle pole motility, yielding asymmetrical spindles that are prone to chromosome missegregation. Collectively, these data demonstrate that Pten, through the Dlg1-binding ability of its PDZ-BD, accumulates phosphorylated Eg5 at duplicated centrosomes to establish symmetrical bipolar spindles that properly segregate chromosomes, and suggest that this function contributes to tumour suppression.

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“…In the Drosophila follicular epithelium, Dlg is important for spindle orientation at metaphase; spindles are misoriented in cells homozygous for the mutant allele dlg 1P20 , which encodes a truncated form of Dlg missing approximately one-third of the GUK domain (Bellaïche et al, 2001;Bergstralh et al, 2013). This role is likely to be conserved, as RNAi-mediated depletion of Dlg in the chick neuroepithelium causes spindle misorientation at metaphase and, less severely, at anaphase (Saadaoui et al, 2014). However, and as we discuss below, precisely how Dlg might function during spindle orientation is unclear.…”

Section: Diverse Roles For Discs Largementioning

confidence: 99%

“…Likewise, work in MDCK cells shows that the phosphorylation site (serine 401) that facilitates binding between Dlg and LGN/Pins is required to exclude cortical LGN from the apical cortex; when S401 is converted to alanine, LGN is not strictly lateral but spreads around the entire cortex (Hao et al, 2010). Similarly, though not identically, conversion of S401 to alanine prevents a truncated LGN (lacking the TPRs) from becoming completely cortical in chick neuroepithelial cells; the truncated protein is instead partially cytoplasmic, suggesting that Dlg works in cooperation with another localization factor, probably Gαi (Saadaoui et al, 2014). Cumulatively, these results suggest that the interaction between phosphorylated Pins and the GUK domain of Dlg helps to localize Pins to the lateral cortex of epithelial cells during mitosis (Fig.…”

Section: Dlg Can Provide a Cortical Cue For Pinsmentioning

confidence: 99%

Spindle orientation: a question of complex positioning

2017

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The direction in which a cell divides is determined by the orientation of its mitotic spindle at metaphase. Spindle orientation is therefore important for a wide range of developmental processes, ranging from germline stem cell division to epithelial tissue homeostasis and regeneration. In multiple cell types in multiple animals, spindle orientation is controlled by a conserved biological machine that mediates a pulling force on astral microtubules. Restricting the localization of this machine to only specific regions of the cortex can thus determine how the mitotic spindle is oriented. As we review here, recent findings based on studies in tunicate, worm, fly and vertebrate cells have revealed that the mechanisms for mediating this restriction are surprisingly diverse.

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Dlg1 controls planar spindle orientation in the neuroepithelium through direct interaction with LGN

Abstract: Dlg1 recruits LGN to the cortex of cells in the chick neuroepithelium and may provide instructive cues that drive planar spindle orientation.

Cited by 64 publications

References 42 publications

Tissue-Intrinsic Tumor Hotspots: Terroir for Tumorigenesis

Tissue-Intrinsic Tumor Hotspots: Terroir for Tumorigenesis

Pten regulates spindle pole movement through Dlg1-mediated recruitment of Eg5 to centrosomes

Spindle orientation: a question of complex positioning

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