A lateral belt of cortical LGN and NuMA guides mitotic spindle movements and planar division in neuroepithelial cells

Peyre, Elise; Jaouen, Florence; Saadaoui, Mehdi; Haren, Laurence; Merdes, Andreas; Durbec, Pascale; Morin, Xavier

doi:10.1083/jcb.201101039

Cited by 135 publications

(194 citation statements)

References 48 publications

(90 reference statements)

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“…In both the spinal cord and cerebral cortex, as in the majority of DT divisions, LGN localizes to lateral domains, where LGN loss increases oblique/perpendicular divisions, suggesting that LGN normally promotes planar divisions (Morin et al, 2007;Konno et al, 2008;Peyre et al, 2011;Shitamukai et al, 2011). However, in epidermis, we and others have shown that LGN forms an apical complex with Insc, Gαi3, NuMA, dynactin and Par3 and that LGN loss leads to loss of perpendicular divisions, impaired Notch signaling and lethal defects in epidermal barrier formation and differentiation (Lechler and Fuchs, 2005;Poulson and Lechler, 2010;Williams et al, 2011Williams et al, , 2014.…”

Section: Discussionmentioning

confidence: 99%

LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development

et al. 2016

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Oral epithelia protect against constant challenges by bacteria, viruses, toxins and injury while also contributing to the formation of ectodermal appendages such as teeth, salivary glands and lingual papillae. Despite increasing evidence that differentiation pathway genes are frequently mutated in oral cancers, comparatively little is known about the mechanisms that regulate normal oral epithelial development. Here, we characterize oral epithelial stratification and describe multiple distinct functions for the mitotic spindle orientation gene LGN (Gpsm2) in promoting differentiation and tissue patterning in the mouse oral cavity. Similar to its function in epidermis, apically localized LGN directs perpendicular divisions that promote stratification of the palatal, buccogingival and ventral tongue epithelia. Surprisingly, however, in dorsal tongue LGN is predominantly localized basally, circumferentially or bilaterally and promotes planar divisions. Loss of LGN disrupts the organization and morphogenesis of filiform papillae but appears to be dispensable for embryonic hair follicle development. Thus, LGN has crucial tissuespecific functions in patterning surface ectoderm and its appendages by controlling division orientation.

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Section: Discussionmentioning

confidence: 99%

LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development

et al. 2016

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“…Several prominent tumor suppressor proteins, including APC, Dlg, VHL (Thoma et al, 2010;Thoma et al, 2009) and LKB1, regulate spindle orientation ( Table 1), suggesting that spindle misorientation might contribute to tumor development (Pease and Tirnauer, 2011). Neurogenesis requires control of cell division orientation in neuroprogenitors at specific developmental stages (Lancaster and Knoblich, 2012) to balance proliferative and neurogenic outcomes (Konno et al, 2008;Peyre et al, 2011). Mutations in the spindle orientation regulators LIS1 (PAFAH1B1) and HTT manifest in Type I lissencephaly and Huntington's disease, respectively.…”

Section: Reviewmentioning

confidence: 99%

“…1C). Cortical spindle orientation cues in SOPs localize through an evolutionarily conserved mechanism known as planar (Lancaster and Knoblich, 2012) to balance proliferative and neurogenic outcomes (Konno et al, 2008;Peyre et al, 2011). Mutations in the spindle orientation regulators LIS1 (PAFAH1B1) and HTT manifest in Type I lissencephaly and Huntington's disease, respectively.…”

mentioning

confidence: 99%

Molecular pathways regulating mitotic spindle orientation in animal cells

2013

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Orientation of the cell division axis is essential for the correct development and maintenance of tissue morphology, both for symmetric cell divisions and for the asymmetric distribution of fate determinants during, for example, stem cell divisions. Oriented cell division depends on the positioning of the mitotic spindle relative to an axis of polarity. Recent studies have illuminated an expanding list of spindle orientation regulators, and a molecular model for how cells couple cortical polarity with spindle positioning has begun to emerge. Here, we review both the wellestablished spindle orientation pathways and recently identified regulators, focusing on how communication between the cell cortex and the spindle is achieved, to provide a contemporary view of how positioning of the mitotic spindle occurs.Key words: Spindle, Microtubules, Oriented cell division, Polarity, Mitosis, Centrosome IntroductionAll multicellular animals are tasked with two fundamental developmental challenges: generating cellular diversity and forming three-dimensional tissues, both of which initiate from a singlecelled zygote. Cellular diversity is spawned by cell divisions yielding non-identical daughters, and tissue morphogenesis is established through the precise three-dimensional arrangement of cell divisions that form the overall architecture of the organism. Both of these essential challenges are resolved in part through oriented cell division, which regulates embryogenesis, organogenesis and cellular differentiation. Notably, oriented cell divisions, and hence asymmetric cell divisions, remain crucial throughout adulthood as well, functioning as the basis for tissue homeostasis during growth and wound repair. One primary feature of oriented cell division is the proper positioning of the mitotic spindle relative to a defined polarity axis. In principle, spindle orientation is achieved through signaling pathways that provide a molecular link between the cell cortex and spindle microtubules. These pathways are thought to elicit both static connections and dynamic forces on the spindle to achieve the desired orientation prior to cell division. Although our knowledge of the signaling molecules involved in this process and our understanding of how they each function at the molecular level remain limited, collective efforts over the years have shed light on the importance of spindle orientation to animal development and function. Moreover, emerging evidence shows an association between improper spindle orientation and a number of developmental diseases as well as tumor formation. The study of spindle orientation is therefore fundamental to both developmental biology and human disease.Over a century ago, Oscar Hertwig discovered that sea urchin embryos biased the orientation of the mitotic spindle along their long axis, which led to a model (the 'Hertwig Rule') in which cells orient divisions in response to mechanical forces (Hertwig, 1884). The Hertwig model stated that mechanical regulation was the primary determinant of spindle orien...

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“…An original model for mInsc proposed that it connects the nuclear mitotic apparatus protein (NuMA)-Leu-Gly-Asn repeat-enriched protein (LGN) complex to the apically localized Par-3/Par-6/aPKC complex (20). The NuMA-LGN complex is located around the cell equator and is instructive for orienting the mitotic spindle horizontally (21)(22)(23). More recent biochemical and structural analyses, however, have demonstrated that mInsc and NuMA are mutually exclusive interaction partners of LGN and that mInsc is able to displace NuMA from its LGN binding site (24,25).…”

Section: Significancementioning

confidence: 99%

Analysis and modeling of mitotic spindle orientations in three dimensions

Jüschke

Xie

Postiglione

et al. 2013

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

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The orientation of the mitotic spindle determines the relative size and position of the daughter cells and influences the asymmetric inheritance of localized cell fate determinants. The onset of mammalian neurogenesis, for example, coincides with changes in spindle orientation. To address the functional implications of this and related phenomena, precise methods for determining the orientation of the mitotic spindle in complex tissues are needed. Here, we present methodology for the analysis of spindle orientation in 3D. Our method allows statistical analysis and modeling of spindle orientation and involves two parameters for horizontal and vertical bias that can unambiguously describe the distribution of spindle orientations in an experimental sample. We find that 3D analysis leads to systematically different results from 2D analysis and, surprisingly, truly random spindle orientations do not result in equal numbers of horizontal and vertical orientations. We show that our method can describe the distribution of spindle orientation angles under different biological conditions. As an example of biological application we demonstrate that the adapter protein Inscuteable (mInsc) can actively promote vertical spindle orientation in apical progenitors during mouse neurogenesis.

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A lateral belt of cortical LGN and NuMA guides mitotic spindle movements and planar division in neuroepithelial cells

Abstract: Knockdown or mislocalization of LGN complex components disrupts the stereotypic biphasic spindle movements regulating planar cell division and neuroepithelial structure in chick embryos.

Cited by 135 publications

References 48 publications

LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development

LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development

Molecular pathways regulating mitotic spindle orientation in animal cells

Analysis and modeling of mitotic spindle orientations in three dimensions

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