On the origin of universal cell shape variability in a confluent epithelial monolayer

  1. Souvik Sadhukhan
  2. Saroj Nandi  Is a corresponding author
  1. Tata Institute of Fundamental Research, India

Abstract

Cell shape is fundamental in biology. The average cell shape can influence crucial biological functions, such as cell fate and division orientation. But cell-to-cell shape variability is often regarded as noise. In contrast, recent works reveal that shape variability in diverse epithelial monolayers follows a nearly universal distribution. However, the origin and implications of this universality remain unclear. Here, assuming contractility and adhesion are crucial for cell shape, characterized via aspect ratio (r), we develop a mean-field analytical theory for shape variability. We find that all the system-specific details combine into a single parameter α that governs the probability distribution function (PDF) of r; this leads to a universal relation between the standard deviation and the average of r. The PDF for the scaled r is not strictly but nearly universal. In addition, we obtain the scaled area distribution, described by the parameter μ, α and μ together can distinguish the effects of changing physical conditions, such as maturation, on different system properties. We have verified the theory via simulations of two distinct models of epithelial monolayers and with existing experiments on diverse systems. We demonstrate that in a confluent monolayer, average shape determines both the shape variability and dynamics. Our results imply that cell shape distribution is inevitable, where a single parameter describes both statics and dynamics and provides a framework to analyze and compare diverse epithelial systems. In contrast to existing theories, our work shows that the universal properties are consequences of a mathematical property and should be valid in general, even in the fluid regime.

Data availability

We have uploaded the source files of the simulation data and the Mathematica analysis files in Dryad.

The following data sets were generated

Article and author information

Author details

  1. Souvik Sadhukhan

    TIFR Centre for Interdisciplinary Sciences, Tata Institute of Fundamental Research, Hyderabad, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0926-6601
  2. Saroj Nandi

    TIFR Centre for Interdisciplinary Sciences, Tata Institute of Fundamental Research, Hyderabad, India
    For correspondence
    saroj@tifrh.res.in
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0977-1947

Funding

Department of Atomic Energy, Government of India (RTI 4007)

  • Souvik Sadhukhan
  • Saroj Nandi

Science and Engineering Research Board (SRG/2021/002014)

  • Saroj Nandi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Karsten Kruse, University of Geneva, Switzerland

Version history

  1. Preprint posted: August 21, 2021 (view preprint)
  2. Received: December 15, 2021
  3. Accepted: December 22, 2022
  4. Accepted Manuscript published: December 23, 2022 (version 1)
  5. Version of Record published: January 11, 2023 (version 2)

Copyright

© 2022, Sadhukhan & Nandi

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,944
    Page views
  • 251
    Downloads
  • 4
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Souvik Sadhukhan
  2. Saroj Nandi
(2022)
On the origin of universal cell shape variability in a confluent epithelial monolayer
eLife 11:e76406.
https://doi.org/10.7554/eLife.76406

Further reading

    1. Chromosomes and Gene Expression
    2. Developmental Biology
    Virginia L Pimmett, Mounia Lagha
    Insight

    Imaging experiments reveal the complex and dynamic nature of the transcriptional hubs associated with Notch signaling.

    1. Cell Biology
    2. Developmental Biology
    Simon Schneider, Andjela Kovacevic ... Hubert Schorle
    Research Article

    Cylicins are testis-specific proteins, which are exclusively expressed during spermiogenesis. In mice and humans, two Cylicins, the gonosomal X-linked Cylicin 1 (Cylc1/CYLC1) and the autosomal Cylicin 2 (Cylc2/CYLC2) genes, have been identified. Cylicins are cytoskeletal proteins with an overall positive charge due to lysine-rich repeats. While Cylicins have been localized in the acrosomal region of round spermatids, they resemble a major component of the calyx within the perinuclear theca at the posterior part of mature sperm nuclei. However, the role of Cylicins during spermiogenesis has not yet been investigated. Here, we applied CRISPR/Cas9-mediated gene editing in zygotes to establish Cylc1- and Cylc2-deficient mouse lines as a model to study the function of these proteins. Cylc1 deficiency resulted in male subfertility, whereas Cylc2-/-, Cylc1-/yCylc2+/-, and Cylc1-/yCylc2-/- males were infertile. Phenotypical characterization revealed that loss of Cylicins prevents proper calyx assembly during spermiogenesis. This results in decreased epididymal sperm counts, impaired shedding of excess cytoplasm, and severe structural malformations, ultimately resulting in impaired sperm motility. Furthermore, exome sequencing identified an infertile man with a hemizygous variant in CYLC1 and a heterozygous variant in CYLC2, displaying morphological abnormalities of the sperm including the absence of the acrosome. Thus, our study highlights the relevance and importance of Cylicins for spermiogenic remodeling and male fertility in human and mouse, and provides the basis for further studies on unraveling the complex molecular interactions between perinuclear theca proteins required during spermiogenesis.