A Caltech Library Service

On the origins of the mitotic shift in proliferating cell layers

Gibson, William T. and Rubinstein, Boris Y. and Meyer, Emily J. and Veldhuis, James H. and Brodland, G. Wayne and Nagpal, Radhika and Gibson, Matthew C. (2014) On the origins of the mitotic shift in proliferating cell layers. Theoretical Biology and Medical Modelling, 11 . Art. No. 26. ISSN 1742-4682. PMCID PMC4048254.

PDF - Published Version
Creative Commons Attribution.

PDF (Figure 1) - Supplemental Material
Creative Commons Public Domain Dedication.

PDF (Figure 2) - Supplemental Material
Creative Commons Public Domain Dedication.


Use this Persistent URL to link to this item:


Background: During plant and animal development, monolayer cell sheets display a stereotyped distribution of polygonal cell shapes. In interphase cells these shapes range from quadrilaterals to decagons, with a robust average of six sides per cell. In contrast, the subset of cells in mitosis exhibits a distinct distribution with an average of seven sides. It remains unclear whether this ‘mitotic shift’ reflects a causal relationship between increased polygonal sidedness and increased division likelihood, or alternatively, a passive effect of local proliferation on cell shape. Methods: We use a combination of probabilistic analysis and mathematical modeling to predict the geometry of mitotic polygonal cells in a proliferating cell layer. To test these predictions experimentally, we use Flp-Out stochastic labeling in the Drosophila wing disc to induce single cell clones, and confocal imaging to quantify the polygonal topologies of these clones as a function of cellular age. For a more generic test in an idealized cell layer, we model epithelial sheet proliferation in a finite element framework, which yields a computationally robust, emergent prediction of the mitotic cell shape distribution. Results: Using both mathematical and experimental approaches, we show that the mitotic shift derives primarily from passive, non-autonomous effects of mitoses in neighboring cells on each cell’s geometry over the course of the cell cycle. Computationally, we predict that interphase cells should passively gain sides over time, such that cells at more advanced stages of the cell cycle will tend to have a larger number of neighbors than those at earlier stages. Validating this prediction, experimental analysis of randomly labeled epithelial cells in the Drosophila wing disc demonstrates that labeled cells exhibit an age-dependent increase in polygonal sidedness. Reinforcing these data, finite element simulations of epithelial sheet proliferation demonstrate in a generic framework that passive side-gaining is sufficient to generate a mitotic shift. Conclusions: Taken together, our results strongly suggest that the mitotic shift reflects a time-dependent accumulation of shared cellular interfaces over the course of the cell cycle. These results uncover fundamental constraints on the relationship between cell shape and cell division that should be general in adherent, polarized cell layers.

Item Type:Article
Related URLs:
URLURL TypeDescription DOIArticle Files CentralArticle
Additional Information:© 2014 Gibson et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated. Received: 4 November 2013; Accepted: 5 May 2014; Published: 27 May 2014. We thank Norbert Perrimon for critical comments and discussion. We are grateful to the Stowers Institute and to HHMI for financial support. WTG is a fellow of the Jane Coffin Childs foundation for medical research. Authors’ contributions: WTG, BYR, EJM, and JHV performed research. WTG, BYR, MCG designed research. GWB, RN, and MCG supervised research. WTG, BYR, and MCG wrote the paper. WTG and BYR contributed equally to this work. All authors read and approved the final manuscript. Competing interest: The authors declare that they have no competing interests.
Funding AgencyGrant Number
Stowers InstituteUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Jane Coffin Childs FoundationUNSPECIFIED
Subject Keywords:Cell topology; Epithelial morphogenesis; Mathematical modeling; Mitosis; Developmental biology
PubMed Central ID:PMC4048254
Record Number:CaltechAUTHORS:20140710-124907245
Persistent URL:
Official Citation:Gibson et al.: On the origins of the mitotic shift in proliferating cell layers. Theoretical Biology and Medical Modelling 2014 11:26
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:47144
Deposited By: Tony Diaz
Deposited On:10 Jul 2014 20:06
Last Modified:03 Oct 2019 06:50

Repository Staff Only: item control page