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Spindle positioning and its impact on vertebrate tissue architecture and cell fate

Nature Reviews Molecular Cell Biology volume 22, pages 691–708 (2021)Cite this article

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Abstract

In multicellular systems, oriented cell divisions are essential for morphogenesis and homeostasis as they determine the position of daughter cells within the tissue and also, in many cases, their fate. Early studies in invertebrates led to the identification of conserved core mechanisms of mitotic spindle positioning centred on the Gαi–LGN–NuMA–dynein complex. In recent years, much has been learnt about the way this complex functions in vertebrate cells. In particular, studies addressed how the Gαi–LGN–NuMA–dynein complex dynamically crosstalks with astral microtubules and the actin cytoskeleton, and how it is regulated to orient the spindle according to cellular and tissue-wide cues. We have also begun to understand how dynein motors and actin regulators interact with mechanosensitive adhesion molecules sensing extracellular mechanical stimuli, such as cadherins and integrins, and with signalling pathways so as to respond to extracellular cues instructing the orientation of the division axis in vivo. In this Review, with the focus on epithelial tissues, we discuss the molecular mechanisms of mitotic spindle orientation in vertebrate cells, and how this machinery is regulated by epithelial cues and extracellular signals to maintain tissue cohesiveness during mitosis. We also outline recent knowledge of how spindle orientation impacts tissue architecture in epithelia and its emerging links to the regulation of cell fate decisions. Finally, we describe how defective spindle orientation can be corrected or its effects eliminated in tissues under physiological conditions, and the pathological implications associated with spindle misorientation.

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Fig. 1: Morphological changes instructing spindle orientation during mitotic progression.
Fig. 2: Working principles of cortical force generators.
Fig. 3: Molecular mechanisms of oriented planar cell divisions.
Fig. 4: Roles of regulated spindle orientation in controlling tissue architecture.
Fig. 5: Cues implicated in asymmetric cell fate acquisition.
Fig. 6: Tumorigenic consequences of spindle misalignment and tissue responses to ameliorate spindle misorientation.

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Acknowledgements

This work was supported by a grant to M.M. from the Italian Association for Cancer Research (AIRC) (IG-25098), and partially supported by the Italian Ministry of Health with Ricerca Corrente and 5×1000 funds. This work was also supported by grants R01-AR067203, R01-DK117981 and R01-AR055926 from the US National Institutes of Health to T.L.

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Authors and Affiliations

  1. Department of Dermatology, Duke University Medical Center, Durham, NC, USA

    Terry Lechler

  2. Department of Cell Biology, Duke University Medical Center, Durham, NC, USA

    Terry Lechler

  3. Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy

    Marina Mapelli

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  1. Terry Lechler
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  2. Marina Mapelli
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The authors contributed equally to all aspects of the article.

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Glossary

Kinetochores

Protein complexes that assemble on the centromeres of chromosomes that capture microtubules of the mitotic spindle, allowing chromosome capture and segregation.

Astral microtubules

Populations of microtubules in the mitotic spindle that do not attach to kinetochores. A subset of these interact with the cell cortex and are essential for spindle positioning.

Cell cortex

A layer of actomyosin, F-actin and other cytoplasmic proteins forming on the inner side of the cell membrane and is responsible for the mitotic rounding.

Neuroblasts

Neural stem cells in Drosophila melanogaster development.

Dynamic instability

A dynamical switch between growing and shrinking phases occurring at the microtubule plus and minus ends.

Xmap215/Stu2 family proteins

Xmap215 in frogs (named Stu2 in budding yeast and TOG in human cells) is a protein containing TOG domains that bind tubulin and regulate microtubule dynamics, primarily by promoting microtubule growth.

CLIP-170

Cytoplasmic linker protein 170, a protein containing two CAP-Gly domains binding to tubulin.

CDK1

Cyclin-dependent-kinase 1, a kinase activated by cyclin B to promote G2–M transition. It is then inactivated upon bipolar kinetochore attachment by APC-dependent degradation of cyclin B, which promotes metaphase to anaphase transition.

CAP-Gly-containing proteins

Proteins containing a cytoskeleton-associated protein glycine-rich domain associating with EEY motifs.

Dynactin

A macromolecular complex of 23 subunits acting as a cofactor for the microtubule motor cytoplasmic dynein 1.

Heterotrimeric G proteins

Membrane-associated G proteins consisting of trimers of Gα–Gβ–Gγ subunits, with a GTPase Gα subunit. Upon extracellular stimulation, transmembrane G-protein-coupled receptors act as a guanine nucleotide exchange factor for the Gα subunits, resulting in G-protein signalling activation.

Dynein adaptor

A coiled-coil protein promoting the formation of dynein–dynactin complexes and the processive movements of the dynein complex on the microtubule tracks.

Tetratricopeptide-repeat (TPR) domain

Thirty-four-residue-long repeats consisting of two antiparallel helices connected by a short loop, generally organized in superhelical arrays.

GoLoco motifs

Nineteen-residue-long motifs found in G-protein regulators acting as guanine-dissociation inhibitors of Gαi.

G-protein-coupled receptor

(GPCR). A cell surface seven-pass-transmembrane receptor activating cellular response upon binding to extracellular signalling molecules.

TOG domains

Conserved tubulin-binding domains consisting of six HEAT (that is, helix–turn–helix repeats present in huntingtin, elongation factor 3, protein phosphatase PP2A and the kinase Tor1) repeats.

4.1R

A member of the F-actin-binding 4.1 family that binds to NuMA in mitosis.

CC1-like box motif

A motif conforming to the CC1 box present in several dynein-activating adaptors but carrying a frameshift in the position of the Ala-Ala doublet and lacking the Gly in the central A-A-X-X-G sequence.

Aurora A

A mitotic kinase activated by microtubule-associated protein TPX2 that assists mitotic progression by phosphorylating key substrates at the spindle poles.

PLK1

Polo-like kinase 1, a centrosomal kinase promoting spindle pole maturation and spindle assembly.

Ran–GTP

A small G protein that plays roles in nuclear import and export as well as in regulating chromatin-dependent microtubule nucleation in mitosis.

Non-canonical WNT signalling

Signalling through secreted WNT proteins that activate pathways other than stabilization of β-catenin.

Mother centrosome

Centrosomes consist of a pair of centrioles and the pericentriolar material. The mother centrosome contains one centriole that is more than one cell cycle old, and another that was assembled during the current cell cycle, while the daughter centrosomes contain one centriole that was assembled in the previous cell cycle and one that was assembled in the current cell cycle.

Nectin

A cell–cell adhesion molecule organizing epithelial junctions and interacting intracellularly with the F-actin-binding protein afadin.

ERM (ezrin–radixin–moesin) family proteins

Conserved proteins consisting of a FERM domain interacting with membrane-associated proteins and an F-actin-binding domain crossliking actin filaments at the mitotic cortex. Moesin codes for a microtubule-binding domain stabilizing astral microtubules at the cortex.

Ste20-like kinase

A Ser/Thr kinase that in mitosis activates ERM (ezrin–radixin–moesin) proteins to promote spindle orientation via LGN–NuMA cortical enrichment.

Myosin X

A microtubule-binding myosin with an unconventional dimeric motor domain.

Caveola

An invagination of the plasma membrane about 50–100 nm in diameter that has been implicated in clathrin-independent endocytosis. In addition, subcortical caveolin-rich patches generate a proteinaceous platform for astral microtubule anchoring and mechanotransduction.

Focal adhesion

Integrin-containing macromolecular complexes mediating mechanical contacts between intracellular F-actin and the extracellular matrix.

Basement membrane

A thin flexible sheet-like extracellular matrix found between the basal site of epithelial layers and connective tissues, providing support and signalling.

Catenins

A family of proteins that bind to the intracellular portion of cadherins at adherens junctions and to the actin cytoskeleton.

Notum

The dorsal portion of the thoracic segment of insects.

Scribble polarity complex

A macromolecular complex consisting of the evolutionarily conserved proteins Scribble, DLG and LGL localizing at the cytoplasmic site of the lateral membrane in polarized epithelial cells.

Epiboly

One of the types of cell movement occurring during zebrafish gastrulation.

VEGF

Vascular endothelial growth factor, a growth factor that promotes angiogenesis.

Immune synapse

The site of connection between an antigen-presenting cell and a T or B lymphocyte.

Intermediate filament cytoskeleton

A cytoskeleton element comprising filaments (8–10 nm thick) made up of diverse and cell type-specific proteins, such as keratins and vimentin.

Primary cilium

A microtubule-based structure that extends from the cell and that can act as a sensory antenna and signalling centre.

Polar body

A small haploid cell that results from meiotic divisions of the oocyte.

Chudley–McCollough syndrome

An autosomal recessive condition characterized by hearing loss and brain malformations.

Stereocilia

F-actin-rich protrusions of hair cells of the inner ear that sense fluid flow and are essential for hearing and balance.

Planar cell polarity

Polarization of a field of cells within the plane of the cell sheet.

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Lechler, T., Mapelli, M. Spindle positioning and its impact on vertebrate tissue architecture and cell fate. Nat Rev Mol Cell Biol 22, 691–708 (2021). https://doi.org/10.1038/s41580-021-00384-4

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