Mechanical regulation of cell size, fate, and behavior during asymmetric cell division
Introduction
Asymmetric cell division (ACD) is a conserved mechanism evolved to generate cellular diversity. A key principle of ACD is the establishment of distinct sibling cell fates by mechanisms linked to mitosis. Differential sibling cell fates can be acquired through biased segregation of macromolecules, differential partitioning of organelles, and/or variations in sibling cell size or shape [1]. ACD is preceded by symmetry breaking events, often induced through precise spatiotemporal regulation of the cytoskeleton. Modulating the contractility of actomyosin underneath the plasma membrane (cell cortex, hereafter) can induce cortex and membrane flows, affecting cytoplasmic streaming and/or influence hydrostatic pressure. These intrinsic mechanical forces, generated by the cytoskeleton, can modify cell size, morphology, spindle orientation, and positioning, all of which can ultimately impact cell fate bias. However, how mechanical and biochemical cues intertwine to induce symmetry breaking events is an open question in the field. Similarly, whether and how forces generated by the cytoskeleton directly translate into cell fate bias is unclear. Cells are also exposed to extrinsic mechanical cues such as substrate stiffness, shear stress, compression, or intercellular adhesive forces, impacting cell morphology and size. How extrinsic cues are translated into cell fate bias during ACD remains to be resolved. Here, we will review recent literature on how cell intrinsic and extrinsic mechanical forces affect stem cells and ACD, focusing primarily on metazoan systems.
Section snippets
The mechanobiology of sibling cell size asymmetry
A clear manifestation of ACD is the formation of unequal sized sibling cells, here, also referred to as physical or sibling cell size asymmetry. Sibling cell size asymmetry can be generated through various cell intrinsic mechanical forces such as (1) asymmetric spindle positioning through cortical pulling or cytoplasmic pushing forces, (2) biased cortical expansion, or (3) biased retraction of cortical lobes. Several recent studies illustrate how molecular modifications of the cytoskeleton
Mechanosensation and cell fate responses in vivo
How asymmetrically dividing cells sense, transmit, and interpret mechanical cues is unclear but mechanosensitive ion channels and transcriptional coactivators provide a conceptual framework. For instance, mechanical cues can be transmitted by the actin cytoskeleton via the coactivators yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), translating mechanical stresses into transcriptional responses [28]. In the early mouse blastocyst, a symmetry breaking
Extracellular forces influencing oriented and ACD
In multicellular contexts, a dividing cell receives numerous physical and chemical cues from multiple neighboring cells, influencing the final division axis and the position of the resulting sibling cells. For instance, during early development of C. elegans and mouse embryos, physical contact was shown to orient cell division and myosin flow. Physical contact induces myosin's anisotropic flows, sufficient to generate membrane movements, resulting in a cell surface torque that orients the cell
Conclusions
The influence of mechanical forces on cell fate has now been explored in various cell types and cell contexts. However, how these forces are sensed and ultimately relayed demands further exploration. In addition, how mechanical forces specifically influence or regulate symmetry breaking events under physiological conditions needs to be defined. To this end, tools must be established to measure, manipulate, and/or induce mechanical forces in vivo. Furthermore, to clearly delineate whether
Conflict of interest statement
Nothing declared.
Acknowledgements
The authors thank members of the Cabernard laboratory for helpful discussions. This work was supported by the National Institutes of Health (NIH; 1R01GM126029-03) and a Research Scholar grant from the American Cancer Society (ACS; 130285-RSG-16-25301-CSM). The authors apologize to all the researchers and authors whose work they were unable to cite because of space constraints.
References (52)
- et al.
Mechanisms of asymmetric cell division: two Bs or not two Bs, that is the question
Cell
(1992) - et al.
Evolutionary modification of AGS protein contributes to formation of micromeres in sea urchins
Nat Commun
(2019) The cortical force-generating machinery: how cortical spindle-pulling forces are generated
Curr Opin Cell Biol
(2019)- et al.
Asymmetric division through a reduction of microtubule centering forces
J Cell Biol
(2018) Mechanisms of spindle positioning: lessons from worms and mammalian cells
Biomolecules
(2019)- et al.
Assembly and positioning of the oocyte meiotic spindle
Annu Rev Cell Dev Biol
(2018) - et al.
Dynamic organelle distribution initiates actin-based spindle migration in mouse oocytes
Nat Commun
(2020) - et al.
Cdk1 inactivation induces post-anaphase-onset spindle migration and membrane protrusion required for extreme asymmetry in mouse oocytes
Nat Commun
(2018) - et al.
Dynamic maintenance of asymmetric meiotic spindle position through Arp2/3-complex-driven cytoplasmic streaming in mouse oocytes
Nat Cell Biol
(2011) - et al.
Symmetry breaking in hydrodynamic forces drives meiotic spindle rotation in mammalian oocytes
Sci Adv
(2020)
Glotzer M: spatiotemporal regulation of RhoA during cytokinesis
Curr Biol
Drosophila melanogaster neuroblasts: a model for asymmetric stem cell divisions
Results Probl Cell Differ
Asymmetric cortical extension shifts cleavage furrow position in Drosophila neuroblasts
Mol Biol Cell
A spindle-independent cleavage furrow positioning pathway
Nature
Asymmetrically dividing Drosophila neuroblasts utilize two spatially and temporally independent cytokinesis pathways
Nat Commun
Spatio-temporally separated cortical flows and spindle geometry establish physical asymmetry in fly neural stem cells
Nat Commun
Cell polarity regulates biased Myosin activity and dynamics during asymmetric cell division via Drosophila Rho kinase and protein kinase N
Spatiotemporally controlled Myosin relocalization and internal pressure cause biased cortical extension to generate sibling cell size asymmetry
Iscience
Aurora-A breaks symmetry in contractile actomyosin networks independently of its role in centrosome maturation
Dev Cell
Aurora A depletion reveals centrosome-independent polarization mechanism in Caenorhabditis elegans
Elife
Mollusc models I. The snail Ilyanassa
Curr Opin Genet Dev
Cytoskeletal polarization and cytokinetic signaling drives polar lobe formation in spiralian embryos
Dev Biol
Organogenesis in normal and lobeless embryos of the marine prosobranch gastropodIlyanassa obsoleta
J Morphol
Experimental studies on germinal localization in Ilyanassa. I. The role of the polar lobe in determination of the cleavage pattern and its influence in later development
J Exp Zool
Experimental studies on gasteropod development
Archiv Für Entwicklungsmechanik Der Org
Development of Ilyanassa obsoleta embryos after equal distribution of polar lobe material at first cleavage
Dev Biol
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