Cadherin Adhesion Receptors Orient the Mitotic Spindle during Symmetric Cell Division in Mammalian Epithelia

Oriented cell division is a fundamental determinant of tissue organization. Simple epithelia divide symmetrically in the plane of the monolayer to preserve organ structure during epithelial morphogenesis and tissue turnover. For this to occur, mitotic spindles must be stringently oriented in the Z-axis, thereby establishing the perpendicular division plane between daughter cells. Spatial cues are thought to play important roles in spindle orientation, notably during asymmetric cell division. The molecular nature of the cortical cues that guide the spindle during symmetric cell division, however, is poorly understood. Here we show directly for the first time that cadherin adhesion receptors are required for planar spindle orientation in mammalian epithelia. Importantly, spindle orientation was disrupted without affecting tissue cohesion or epithelial polarity. This suggests that cadherin receptors can serve as cues for spindle orientation during symmetric cell division. We further show that disrupting cadherin function perturbed the cortical localization of APC, a microtubule-interacting protein that was required for planar spindle orientation. Together, these findings establish a novel morphogenetic function for cadherin adhesion receptors to guide spindle orientation during symmetric cell division.

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Cytoplasmic MTOCs control spindle orientation for asymmetric cell division in plants

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1713925114 ◽

2017 ◽

Vol 114 (42) ◽

pp. E8847-E8854 ◽

Cited By ~ 23

Author(s):

Ken Kosetsu ◽

Takashi Murata ◽

Moé Yamada ◽

Momoko Nishina ◽

Joanna Boruc ◽

...

Keyword(s):

Cell Division ◽

Asymmetric Cell Division ◽

Physcomitrella Patens ◽

De Novo ◽

Critical Role ◽

Fine Tuning ◽

Spindle Orientation ◽

Mitotic Apparatus ◽

Division Plane ◽

Division Axis

Proper orientation of the cell division axis is critical for asymmetric cell divisions that underpin cell differentiation. In animals, centrosomes are the dominant microtubule organizing centers (MTOC) and play a pivotal role in axis determination by orienting the mitotic spindle. In land plants that lack centrosomes, a critical role of a microtubular ring structure, the preprophase band (PPB), has been observed in this process; the PPB is required for orienting (before prophase) and guiding (in telophase) the mitotic apparatus. However, plants must possess additional mechanisms to control the division axis, as certain cell types or mutants do not form PPBs. Here, using live imaging of the gametophore of the moss Physcomitrella patens, we identified acentrosomal MTOCs, which we termed “gametosomes,” appearing de novo and transiently in the prophase cytoplasm independent of PPB formation. We show that gametosomes are dispensable for spindle formation but required for metaphase spindle orientation. In some cells, gametosomes appeared reminiscent of the bipolar MT “polar cap” structure that forms transiently around the prophase nucleus in angiosperms. Specific disruption of the polar caps in tobacco cells misoriented the metaphase spindles and frequently altered the final division plane, indicating that they are functionally analogous to the gametosomes. These results suggest a broad use of transient MTOC structures as the spindle orientation machinery in plants, compensating for the evolutionary loss of centrosomes, to secure the initial orientation of the spindle in a spatial window that allows subsequent fine-tuning of the division plane axis by the guidance machinery.

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Asymmetric cell division in fucoid algae: a role for cortical adhesions in alignment of the mitotic apparatus

Journal of Cell Science ◽

10.1242/jcs.114.23.4319 ◽

2001 ◽

Vol 114 (23) ◽

pp. 4319-4328

Author(s):

Sherryl R. Bisgrove ◽

Darryl L. Kropf

Keyword(s):

Cell Division ◽

Asymmetric Cell Division ◽

Cell Cortex ◽

Mitotic Apparatus ◽

Pharmacological Agents ◽

Division Plane ◽

Adhesion Sites ◽

Spindle Poles ◽

Pelvetia Compressa ◽

Two Phases

The first cell division in zygotes of the fucoid brown alga Pelvetia compressa is asymmetric and we are interested in the mechanism controlling the alignment of this division. Since the division plane bisects the mitotic apparatus, we investigated the timing and mechanism of spindle alignments. Centrosomes, which give rise to spindle poles, aligned with the growth axis in two phases – a premetaphase rotation of the nucleus and centrosomes followed by a postmetaphase alignment that coincided with the separation of the mitotic spindle poles during anaphase and telophase. The roles of the cytoskeleton and cell cortex in the two phases of alignment were analyzed by treatment with pharmacological agents. Treatments that disrupted cytoskeleton or perturbed cortical adhesions inhibited pre-metaphase alignment and we propose that this rotational alignment is effected by microtubules anchored at cortical adhesion sites. Postmetaphase alignment was not affected by any of the treatments tested, and may be dependent on asymmetric cell morphology.

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Unequal cleavage in leech embryos: zygotic transcription is required for correct spindle orientation in subset of early blastomeres

Development ◽

10.1242/dev.122.2.599 ◽

1996 ◽

Vol 122 (2) ◽

pp. 599-606

Author(s):

S.T. Bissen ◽

C.M. Smith

Keyword(s):

Cell Division ◽

Early Period ◽

Spindle Orientation ◽

Mitotic Spindles ◽

Maternal Control ◽

Transcription Analysis ◽

Cell Divisions ◽

Zygotic Transcription ◽

Different Types ◽

Alpha Amanitin

Leech embryos undergo invariant sequences of equal and unequal cell divisions to give rise to identifiable progeny cells. While many of the early cleavages are under maternal control, the divisions of a subset of early blastomeres (the large cells of the D' lineage) are perturbed after the inhibition of zygotic transcription. Analysis of the different types of cells produced in embryos injected with the transcriptional inhibitor, alpha-amanitin, revealed that the symmetry of cell division is perturbed in these large D'-derived cells during this early period of development. These cells, which would normally undergo a series of equal and unequal cleavages, always undergo equal cleavages after the inhibition of zygotic transcription. It appears that zygotically transcribed gene product(s) are required in the large cells of the D' lineage to orient the mitotic spindles properly for these unequal cell cleavages.

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Cell shape and intercellular adhesion regulate mitotic spindle orientation

Molecular Biology of the Cell ◽

10.1091/mbc.e19-04-0227 ◽

2019 ◽

Vol 30 (19) ◽

pp. 2458-2468 ◽

Cited By ~ 10

Author(s):

Jingchen Li ◽

Longcan Cheng ◽

Hongyuan Jiang

Keyword(s):

Cell Division ◽

Epithelial Cells ◽

Cell Fate ◽

Cell Shape ◽

Intercellular Adhesion ◽

Shape Anisotropy ◽

Spindle Orientation ◽

Mitotic Spindles ◽

Strong Adhesion ◽

Fate Decision

Cell division orientation plays an essential role in tissue morphogenesis and cell fate decision. Recent studies showed that either cell shape or adhesion geometry can regulate the orientation of mitotic spindles and thereby the cell division orientation. However, how they together regulate the spindle orientation remains largely unclear. In this work, we use a general computational model to investigate the competitive mechanism of determining the spindle orientation between cell shape and intercellular adhesion in epithelial cells. We find the spindle orientation is dominated by the intercellular adhesion when the cell shape anisotropy is small, but dominated by the cell shape when the shape anisotropy is large. A strong adhesion and moderate adhesive size can ensure the planar division of epithelial cells with large apico-basal elongation. We also find the spindle orientation could be perpendicular to the adhesive region when only one side of the cell is adhered to an E-cadherin–coated matrix. But after the cell is compressed, the spindle orientation is governed by the cell shape and the spindle will be parallel to the adhesive region when the cell shape anisotropy is large. Finally, we demonstrate the competition between cell shape and tricellular junctions can also effectively regulate the spindle orientation.

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Asymmetric cell division: Plane but not simple

Current Biology ◽

10.1016/s0960-9822(01)00113-0 ◽

2001 ◽

Vol 11 (6) ◽

pp. R233-R236 ◽

Cited By ~ 13

Author(s):

Paul N. Adler ◽

Job Taylor

Keyword(s):

Cell Division ◽

Asymmetric Cell Division ◽

Division Plane ◽

Cell Division Plane

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Cytokine receptor-Eb1 interaction couples cell polarity and fate during asymmetric cell division

eLife ◽

10.7554/elife.33685 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 8

Author(s):

Cuie Chen ◽

Ryan Cummings ◽

Aghapi Mordovanakis ◽

Alan J Hunt ◽

Michael Mayer ◽

...

Keyword(s):

Stem Cells ◽

Cell Division ◽

Cell Fate ◽

Cell Polarity ◽

Adult Stem Cells ◽

Asymmetric Cell Division ◽

Cytokine Receptor ◽

Spindle Orientation ◽

Germline Stem Cells ◽

Self Renewal

Asymmetric stem cell division is a critical mechanism for balancing self-renewal and differentiation. Adult stem cells often orient their mitotic spindle to place one daughter inside the niche and the other outside of it to achieve asymmetric division. It remains unknown whether and how the niche may direct division orientation. Here we discover a novel and evolutionary conserved mechanism that couples cell polarity to cell fate. We show that the cytokine receptor homolog Dome, acting downstream of the niche-derived ligand Upd, directly binds to the microtubule-binding protein Eb1 to regulate spindle orientation in Drosophila male germline stem cells (GSCs). Dome’s role in spindle orientation is entirely separable from its known function in self-renewal mediated by the JAK-STAT pathway. We propose that integration of two functions (cell polarity and fate) in a single receptor is a key mechanism to ensure an asymmetric outcome following cell division.

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Plk1 regulates spindle orientation by phosphorylating NuMA in human cells

Life Science Alliance ◽

10.26508/lsa.201800223 ◽

2018 ◽

Vol 1 (6) ◽

pp. e201800223 ◽

Cited By ~ 14

Author(s):

Shrividya Sana ◽

Riya Keshri ◽

Ashwathi Rajeevan ◽

Sukriti Kapoor ◽

Sachin Kotak

Keyword(s):

Cell Division ◽

Mitotic Spindle ◽

Molecular Mechanisms ◽

Spindle Pole ◽

Spindle Orientation ◽

Cell Cortex ◽

Division Plane ◽

Evolutionarily Conserved ◽

Cortical Localization ◽

Proper Orientation

Proper orientation of the mitotic spindle defines the correct division plane and is essential for accurate cell division and development. In metazoans, an evolutionarily conserved complex comprising of NuMA/LGN/Gαi regulates proper orientation of the mitotic spindle by orchestrating cortical dynein levels during metaphase. However, the molecular mechanisms that modulate the spatiotemporal dynamics of this complex during mitosis remain elusive. Here, we report that acute inactivation of Polo-like kinase 1 (Plk1) during metaphase enriches cortical levels of dynein/NuMA/LGN and thus influences spindle orientation. We establish that this impact of Plk1 on cortical levels of dynein/NuMA/LGN is through NuMA, but not via dynein/LGN. Moreover, we reveal that Plk1 inhibition alters the dynamic behavior of NuMA at the cell cortex. We further show that Plk1 directly interacts and phosphorylates NuMA. Notably, NuMA-phosphorylation by Plk1 impacts its cortical localization, and this is needed for precise spindle orientation during metaphase. Overall, our finding connects spindle-pole pool of Plk1 with cortical NuMA and answers a long-standing puzzle about how spindle-pole Plk1 gradient dictates proper spindle orientation for error-free mitosis.

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HMMR acts in the PLK1-dependent spindle positioning pathway and supports neural development

eLife ◽

10.7554/elife.28672 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 18

Author(s):

Marisa Connell ◽

Helen Chen ◽

Jihong Jiang ◽

Chia-Wei Kuan ◽

Abbas Fotovati ◽

...

Keyword(s):

Cell Division ◽

Neural Development ◽

Cell Types ◽

Spindle Orientation ◽

Spindle Positioning ◽

Over Expression ◽

Oriented Cell Division ◽

Neonatal Lethality ◽

Cortical Localization ◽

Dependent Pathway

Oriented cell division is one mechanism progenitor cells use during development and to maintain tissue homeostasis. Common to most cell types is the asymmetric establishment and regulation of cortical NuMA-dynein complexes that position the mitotic spindle. Here, we discover that HMMR acts at centrosomes in a PLK1-dependent pathway that locates active Ran and modulates the cortical localization of NuMA-dynein complexes to correct mispositioned spindles. This pathway was discovered through the creation and analysis of Hmmr-knockout mice, which suffer neonatal lethality with defective neural development and pleiotropic phenotypes in multiple tissues. HMMR over-expression in immortalized cancer cells induces phenotypes consistent with an increase in active Ran including defects in spindle orientation. These data identify an essential role for HMMR in the PLK1-dependent regulatory pathway that orients progenitor cell division and supports neural development.

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Robust control of mitotic spindle orientation in the developing epidermis

The Journal of Cell Biology ◽

10.1083/jcb.201008001 ◽

2010 ◽

Vol 191 (5) ◽

pp. 915-922 ◽

Cited By ~ 106

Author(s):

Nicholas D. Poulson ◽

Terry Lechler

Keyword(s):

Cell Division ◽

Robust Control ◽

Progenitor Cells ◽

Mitotic Spindle ◽

Asymmetric Cell Division ◽

Transcriptional Regulator ◽

Spindle Orientation ◽

Control Points ◽

External Cues ◽

Increase Surface Area

Progenitor cells must balance self-amplification and production of differentiated progeny during development and homeostasis. In the epidermis, progenitors divide symmetrically to increase surface area and asymmetrically to promote stratification. In this study, we show that individual epidermal cells can undergo both types of division, and therefore, the balance is provided by the sum of individual cells’ choices. In addition, we define two control points for determining a cell’s mode of division. First is the expression of the mouse Inscuteable gene, which is sufficient to drive asymmetric cell division (ACD). However, there is robust control of division orientation as excessive ACDs are prevented by a change in the localization of NuMA, an effector of spindle orientation. Finally, we show that p63, a transcriptional regulator of stratification, does not control either of these processes. These data have uncovered two important regulatory points controlling ACD in the epidermis and allow a framework for analysis of how external cues control this important choice.

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Ends and middle: global force balance determines septum location in fission yeast

10.1101/520007 ◽

2019 ◽

Author(s):

Xavier Le Goff ◽

Jordi Comelles ◽

Charles Kervrann ◽

Daniel Riveline

Keyword(s):

Cell Division ◽

Fission Yeast ◽

Asymmetric Cell Division ◽

Quantitative Imaging ◽

Force Balance ◽

Radius Of Curvature ◽

Division Plane ◽

Division Site ◽

Global Force ◽

Scaling Arguments

AbstractThe fission yeast cell is shaped as a very regular cylinder ending by hemi-spheres at both cell ends. Its conserved phenotypes are often used as read-outs for classifying interacting genes and protein networks. Using Pascal and Young-Laplace laws, we proposed a framework where scaling arguments predicted shapes. Here we probed quantitatively one of these relations which predicts that the division site would be located closer to the cell end with the larger radius of curvature. By combining genetics and quantitative imaging, we tested experimentally whether altered shapes of cell end correlate with a displaced division site, leading to asymmetric cell division. Our results show that the division site position depends on the radii of curvatures of both ends. This new geometrical mechanism for the proper division plane positioning could be essential to achieve even partitioning of cellular material at each cell division.

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