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Apical Constriction Reversal upon Mitotic Entry Underlies Different Morphogenetic Outcomes of Cell Division

Clint S. Ko, Prateek Kalakuntla, Adam C. Martin

Preprint posted on December 03, 2019 https://www.biorxiv.org/content/10.1101/862821v1

The ins and outs of apical constriction: spatial patterns of mitosis within a contractile tissue regulate tissue invagination

Selected by Grace Lim

Background

The shaping of tissues is regulated by a complex interplay of cellular processes and mechanical forces coordinated across a group of cells1. One such process is apical constriction, whereby cells actively shrink their apical surface area, leading to a variety of morphogenetic outcomes including cell ingression, cell extrusion, and folding of epithelial sheets2. While the underlying dynamics and regulators can differ between systems, apical constriction is thought to be driven by contraction of an apical actomyosin network, in order to generate the force needed to alter cell and tissue geometry2.

This preprint investigates apical constriction-driven tissue morphogenesis in the context of mitotic cells within a contractile epithelium. Although the roles of cell division and apical constriction have both been extensively studied, few studies have considered the relationship between the two processes within the same tissue context. Using the Drosophila mesoderm and ectoderm as a model system amenable to genetic manipulations and both cellular- and tissue-level live imaging, the authors address this question and propose a force-based model explaining the interplay between cell division and apical constriction in regulating furrow formation.

Key findings

Using a tribbles (trbl) mutant that was previously shown to undergo premature mitosis and impaired mesoderm invagination, the authors first performed careful temporal analysis of these key events using live embryo imaging. This revealed that upon mitotic entry, cells increased their apical surface area and failed to undergo apical constriction. Furthermore, the live imaging dataset identified apically constricting cells that then reversed the constriction process to expand their apical surface upon entering mitosis. This suggested strongly that mitotic entry could override mechanisms needed for apical constriction and successful ventral furrow formation.

Closer analysis of regulators of apical constriction showed that the prematurely dividing cells in trbl mutant embryos were unable to accumulate medioapical myosin required for actomyosin contractility. This defect in myosin accumulation was not due to changes in intercellular adhesion, cell shape or apicobasal polarity during mitotic entry, but rather disruption of RhoA activity.

The authors further tested their key conclusions in another contractile tissue context, by comparing mitotic and non-mitotic cells within the same ectoderm tissue ectopically expressing the GPCR ligand folded gastrulation (fog). Ectopic fog expression promotes apical myosin accumulation and apical contractility in the ectoderm. Like in the trbl mutant mesoderm, mitotic cells within the fog overexpression ectoderm showed reduced medioapical myosin and diminished RhoA activity.

More surprisingly, the embryos with ectopic fog expression formed ectopic furrows, in contrast to trbl mutant embryos that failed to undergo tissue invagination. The authors showed that these ectopic furrows formed specifically between the mitotic domains of the fog overexpressing ectoderm, and only when cells in the mitotic domains entered mitosis. Upon mitotic entry, these mitotic domain cells in fact expanded and stretched towards the ectopic furrow, while ectopic furrow cells reduced their apical surface area. Together, this suggests a force imbalance within the contractile tissue whereby mitotic cells temporarily lose medioapical contractility and experience greater pulling forces by neighboring non-mitotic cells to undergo apical expansion, while the contractile non-mitotic cells retain the ability to constrict their apical surfaces and invaginate.

Fig. 6 of Ko et al.: Schematic summarizing the key morphogenetic events
within two different contractile epithelial contexts.

What I like about this preprint

The authors utilize live embryo imaging methods elegantly to tease apart the temporal order of events during mitosis and apical constriction in the context of the Drosophila embryo. As the cellular events investigated in this study were closely linked in time, it was informative to understand the dynamic changes of molecular regulators such as myosin, ROCK and various RhoGEFs that were involved in the apical constriction process.

The authors also went a step further to explore this antagonistic relationship between mitotic entry and apical constriction, first in the context of the trbl mutant mesoderm, and also within native fog overexpressing ectoderm containing both mitotic and non-mitotic cells. The striking ectopic furrow formation in the fog overexpressing ectoderm makes a strong point that 1) mitosis blocks apical constriction, and 2) the temporary loss of contractility in mitotic cells can drive apical constriction in neighboring contractile cells.

Future directions and questions for the authors

  1. RhoA activity is known to be controlled by a combination of RhoGEFs and RhoGAPs, which could be differentially localized within cells to precisely determine where RhoA activity is turned on. Apart from the apical-junctional localization of RhoGEF2 that decreased in cells entering mitosis, have the authors explored other Rho regulators, such as RhoGAPs, that could inhibit Rho activity in the basal part of the cell?
  2. The authors propose a model whereby mitotic entry can promote apical constriction and tissue invagination in adjacent, non-mitotic cells within a contractile epithelium, driven by a force imbalance between mitotic and non-mitotic cells. Have the authors compared the forces exerted between mitotic and non-mitotic cells against those between two mitotic or two non-mitotic cells, for example using laser ablation experiments?
  3. In the context of the preimplantation mouse embryo, apical constriction occurs after division of a neighboring cell in approximately half of observed cases3. It would be interesting to investigate if similar Rho-dependent mechanisms also take place in the mouse embryo.

References

  1. Paluch, E., and Heisenberg, C.-P. (2009). Biology and Physics of Cell Shape Changes in Development. Current Biology 19, R790–R799.
  2. Martin, A.C., and Goldstein, B. (2014). Apical constriction: themes and variations on a cellular mechanism driving morphogenesis. Development 141, 1987–1998.
  3. Samarage, C.R., White, M.D., Álvarez, Y.D., Fierro-González, J.C., Henon, Y., Jesudason, E.C., Bissiere, S., Fouras, A., and Plachta, N. (2015). Cortical Tension Allocates the First Inner Cells of the Mammalian Embryo. Developmental Cell 34, 435–447.

 

Posted on: 13th December 2019

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