Interphase cell morphology defines the mode, symmetry, and outcome of mitosis

Nogare, Damian and Pena, Andreia and Herbert, Shane and Costa, Guilherme and Hulmes, Georgia and CA, Franco and Jones, Gareth Wyn and Appleton, Ellen and Lovegrove, Holly and Giralt-Pujol, Marta and Bentley, Katie and Ghadaouia, Sabrina and Linker, Claudia and Manning, Cerys and Alhashem, Zain and Revell, Christopher and Chitnis, Ajay and Ballestrem, Christoph and Mort, R. L. (2025) Interphase cell morphology defines the mode, symmetry, and outcome of mitosis. Science, 388 (6746). ISSN 0036-8075

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Abstract

INTRODUCTION Tissue formation requires the concerted coordination of diverse cellular processes. For example, the major shifts in cell shape that define tissue architecture frequently occur concomitant with the asymmetric cell divisions that generate tissue heterogeneity. Tight spatiotemporal coupling of distinct morphogenetic events is thus critical to achieving robust tissue assembly. RATIONALE In addition to sculpting tissue form, cell shape remodeling also plays a fundamental role in the control of cell division. Upon mitotic entry, metazoan cells typically adopt a spherical shape following global reorganization of the interphase cytoskeleton. This mitotic rounding both promotes high-fidelity segregation of genetic material and generation of equally sized daughters that symmetrically partition most nongenetic cellular components. Thus, modulation of mitotic rounding would represent an elegant means to switch cells from a symmetric to asymmetric division outcome. However, whether cells have the capacity to tune the extent of their mitotic rounding and how this would influence mitotic symmetry and/or daughter identity remains unclear. Moreover, whether prior shifts in interphase cell morphology have any impact on the extent of mitotic shape remodeling or symmetry of division remains unexplored. We hypothesized that, if shifts in interphase cell morphology can indeed affect mitotic shape remodeling, this could explain the close coupling of morphogenetic shape change with the switches in the symmetry of division observed during tissue building. RESULTS To investigate the codependence of interphase and mitotic cell shape dynamics, we exploited single-cell morphometric analyses of tissue formation in multiple contexts, including blood vessel and neural crest development. These analyses revealed that stereotyped shifts in pre-mitotic cell morphology act as conserved instructive cues that tune the mode, symmetry, and outcome of mitosis. We identified that distinct shifts in mesenchymal-like cell morphology switch cells to an "isomorphic” mode of division, which uncharacteristically evades mitotic rounding and preserves pre-mitotic cell morphology throughout division. Using a combination of micropatterning tools and in vivo live imaging, we revealed that preservation of asymmetries in interphase cell morphology during division also resulted in the maintenance of asymmetric distributions of key signaling factors. Specifically, we found that during isomorphic divisions, Rab4-positive recycling endosomes and their fate-determinant cargo were asymmetrically inherited, thereby generating daughters of differing identities. CONCLUSION These observations uncovered dynamic modulation of the extent of mitotic rounding as a previously unknown trigger for asymmetric cell division. In contrast to the current view, this data suggests that mitotic cell rounding is far from a universal feature of mesenchymal-like cell division and is often elegantly tuned by pre-mitotic cell morphology. Moreover, we identified that cells exploit this phenomenon to functionally couple shifts in interphase shape to the induction of distinct daughter cell identities and behaviours, thereby directing tissue assembly. Thus, morphogenetic cell shape change not only sculpts tissue form but concomitantly generates the cellular diversity underpinning tissue building. Considering that most mesenchymal-like cells exhibit equivalent shape dynamics during tissue remodeling, including metastatic cancer cells, instructive cues encoded in interphase morphology are likely an underappreciated and conserved modulator of mitotic symmetry and cell state heterogeneity in diverse tissue contexts.