Concomitant binding of Afadin to LGN and F-actin directs planar spindle orientation

Carminati, Manuel; Gallini, Sara; Pirovano, Laura; Alfieri, Andrea; Bisi, Sara; Mapelli, Marina

doi:10.1038/nsmb.3152

Cited by 78 publications

(105 citation statements)

References 56 publications

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“…In stereocilia, G α i3-GDP could be tethered at the plasma membrane via its myristoyl and palmitylate moieties, and bound to the C-terminal GoLoco motifs of Gpsm2. This would leave the tetratricopeptide repeats and linker region of Gpsm2 free to bind to various proteins (such as whirlin) to anchor or stabilize them, that could in turn interact with actin or other actin-regulatory proteins41, including Eps8 (refs 19, 22). …”

Section: Discussionmentioning

confidence: 99%

Defective Gpsm2/Gαi3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome

et al. 2017

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Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and vestibular hair cells, causing deafness and balance defects. The G-protein subunit Gαi3, a well-documented partner of Gpsm2, participates in the elongation process, and its absence also causes hearing deficits. We show that Gpsm2 defines an ∼200 nm nanodomain at the tips of stereocilia and this localization requires the presence of Gαi3, myosin 15 and whirlin. Using single-molecule tracking, we report that loss of Gpsm2 leads to decreased outgrowth and a disruption of actin dynamics in neuronal growth cones. Our results elucidate the aetiology of CMCS and highlight a new molecular role for Gpsm2/Gαi3 in the regulation of actin dynamics in epithelial and neuronal tissues.

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Section: Discussionmentioning

confidence: 99%

Defective Gpsm2/Gαi3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome

et al. 2017

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“…This putative inhibitory signal could be another protein or a posttranslational modification that competes with LGN for E-cadherin binding. Alternatively, tensile forces might induce the indirect recruitment of LGN to E-cadherin adhesions through tensionsensitive recruitment of additional, intermediate LGN-interacting proteins that may associate with the E-cadherin complex [e.g., discs large (DLG) (47), Afadin (48), and ezrin, radixin, moesin (ERM) proteins (49)]. However, we did not observe a polarized distribution of any of these proteins in the presence or absence of uniaxial stretch, as we did for LGN (Fig.…”

Section: Discussionmentioning

confidence: 99%

E-cadherin and LGN align epithelial cell divisions with tissue tension independently of cell shape

Hart

Tan

Siemers

et al. 2017

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

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Tissue morphogenesis requires the coordinated regulation of cellular behavior, which includes the orientation of cell division that defines the position of daughter cells in the tissue. Cell division orientation is instructed by biochemical and mechanical signals from the local tissue environment, but how those signals control mitotic spindle orientation is not fully understood. Here, we tested how mechanical tension across an epithelial monolayer is sensed to orient cell divisions. Tension across Madin-Darby canine kidney cell monolayers was increased by a low level of uniaxial stretch, which oriented cell divisions with the stretch axis irrespective of the orientation of the cell long axis. We demonstrate that stretch-induced division orientation required mechanotransduction through E-cadherin cell-cell adhesions. Increased tension on the E-cadherin complex promoted the junctional recruitment of the protein LGN, a core component of the spindle orientation machinery that binds the cytosolic tail of Ecadherin. Consequently, uniaxial stretch triggered a polarized cortical distribution of LGN. Selective disruption of trans engagement of E-cadherin in an otherwise cohesive cell monolayer, or loss of LGN expression, resulted in randomly oriented cell divisions in the presence of uniaxial stretch. Our findings indicate that E-cadherin plays a key role in sensing polarized tensile forces across the tissue and transducing this information to the spindle orientation machinery to align cell divisions.cell-cell adhesion | cell division orientation | mitotic spindle | mechanotransduction

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“…In contrast, other studies suggested that polarity cues provided by adherens junctions could override apical-basal polarity cues to maintain cell division orientation within the epithelial plane and inhibit asymmetric division [41]. Supporting this role of adherens junctions in maintaining symmetric mitotic divisions, a recent study in human epithelial cells provided evidence that Afadin controls planar mitotic orientation within epithelia by binding F-actin and the protein LGN to direct spindle positioning [42]. Our observations that Afadin loss in the developing mammalian cortical neuroepithelium results in increased numbers of non-planar mitotic orientations provide further support for the role of Afadin and adherens junctions in inhibiting asymmetric division.…”

Section: Discussionmentioning

confidence: 99%

Afadin controls cell polarization and mitotic spindle orientation in developing cortical radial glia

et al. 2017

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BackgroundIn developing tissues, cell polarity and tissue architecture play essential roles in the regulation of proliferation and differentiation. During cerebral cortical development, adherens junctions link highly polarized radial glial cells in a neurogenic niche that controls their behavior. How adherens junctions regulate radial glial cell polarity and/or differentiation in mammalian cortical development is poorly understood.ResultsConditional deletion of Afadin, a protein required for formation and maintenance of epithelial tissues, leads to abnormalities in radial glial cell polarity and subsequent loss of adherens junctions. We observed increased numbers of obliquely-oriented progenitor cell divisions, increased exit from the ventricular zone neuroepithelium, and increased production of intermediate progenitors.ConclusionsTogether, these findings indicate that Afadin plays an essential role in regulating apical-basal polarity and adherens junction integrity of radial glial cells, and suggest that epithelial architecture plays an important role in radial glial identity by regulating mitotic orientation and preventing premature exit from the neurogenic niche.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-017-0085-2) contains supplementary material, which is available to authorized users.

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Concomitant binding of Afadin to LGN and F-actin directs planar spindle orientation

Cited by 78 publications

References 56 publications

Defective Gpsm2/Gαi3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome

Defective Gpsm2/Gαi3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome

E-cadherin and LGN align epithelial cell divisions with tissue tension independently of cell shape

Afadin controls cell polarization and mitotic spindle orientation in developing cortical radial glia

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