Morphogenesis: The enigma of cell intercalation

Geometric criteria can be used to assess whether cell intercalation is active or passive during the convergent extension of tissue.
  1. Raphaël Clément  Is a corresponding author
  1. Institut de Biologie du Développement de Marseille, Aix Marseille University, CNRS, France

During embryonic development, living tissues undergo a range of transformations, including massive shape changes. This process, known as morphogenesis, can occur through growth, cell division or cell death, but also through the coordination of internal forces generated by individual cells. Thanks to advances in microscopy and physical biology, much is known about how cells produce such forces and how they integrate on a larger scale to drive robust changes in tissue shape (Heisenberg and Bellaïche, 2013). Yet, it remains a challenge to disentangle which part of the deformation is due to internal forces produced within the considered tissue, and which part is due to the movement of adjacent regions.

Now, in eLife, Fridtjof Brauns, Nikolas Claussen, Eric Wieschaus, and Boris Shraiman report new insights into the mechanisms of tissue convergent extension (Brauns et al., 2024), a process whereby tissues elongate along one axis while contracting along the other, resulting in a longer and narrower shape. Convergent extension is associated with intercalation events during which quartets of cells exchange neighbors. In this process, two cells lose contact with one another, while the other two gain contact as the central interface collapses (Figure 1A). Intercalation allows tissue extension to proceed without accumulating strain at the cellular level. Whether intercalation passively follows tissue extension (for instance caused by another adjacent active region), or is itself an active driver of tissue extension, remains difficult to assess.

Illustration of cell intercalation during convergent extension of tissue.

(A) Intercalating quartet of cells in an epithelial tissue. Two cells gain contact (magenta), and two cells lose contact (cyan) as the central interface collapses. (B) Tension driven (active) versus isogonal (passive) intercalation.

To investigate, the researchers, based at the University of California Santa Barbara and Princeton University, developed a quantitative, model-based analysis framework to study previously published data on fruit fly embryonic development. They focussed on two regions undergoing intercalation events: the germband (an epithelial monolayer that eventually develops into the segmented trunk of the embryo), and the amnioserosa (an extraembryonic epithelial monolayer). They used a technique, called force inference, on intercalating quartets, which allows inferring the tension at cell interfaces based on cell geometry (Roffay et al., 2021). This revealed that collapsing interfaces located between the two cells about to connect, display radically distinct tension dynamics in the germband and the amnioserosa. In the germband, in which myosin activity (a force-producing protein) is known to actively drive intercalation events (Rauzi et al., 2008), tension increases before the interface collapses. In the amnioserosa, however, tension remains constant until collapse.

To make sense of this contrast, Brauns et al. decomposed the strain of intercalating quartets into two components. The passive, isogonal component allows the quartet to deform, such as getting wider or taller, whilst maintaining the same angles, and reflects external forces exerted by adjacent tissues. The active tension component affects how the edges of the quartet are angled, and reflects variations of local interface tensions. During intercalation in the germband, the isogonal component remains constant, while the tension component increases, confirming that active changes in tension drive intercalation. The opposite is found for the amnioserosa. Active tension and passive isogonal strain thus appear as distinct ways to enable cell neighbor exchange in elongating tissues (Figure 1B), with distinct geometric signatures.

Brauns et al. then propose a minimal model in line with recent studies (Dierkes et al., 2014; Sknepnek et al., 2023), which postulates that the amount of myosin increases as tension grows during the collapse of cell interfaces (in other words, a positive feedback on tension). It further assumes that passive tension is dissipated by the turnover of cytoskeletal crosslinkers, which agrees with previous observations (Clément et al., 2017; Khalilgharibi et al., 2019). The absence of the positive tension feedback corresponds to the case of passive intercalation under external stretch. The model qualitatively recapitulates their findings at the quartet scale.

Finally, Brauns et al. compute tension anisotropy and isogonal strain at the embryo scale, which allows the regions of the tissue undergoing active or passive intercalation to be identified. They show that ‘tension bridge’ arrangements (an interface with high tension surrounded by lower tension interfaces) are more efficient at driving intercalation than ‘tension cable’ arrangements (adjacent interfaces aligned due to similarly high levels of tension), because tension bridges require less tension anisotropy to achieve an exchange of neighboring cells.

Overall, the elegant work of Brauns et al. proposes simple geometric criteria for assessing whether intercalation is active or passive and makes explicit the conditions for intercalation. However, important questions remain. First, the tissue-scale analysis remains essentially qualitative at this stage. Second, it has been reported that germband extension can still proceed when the rate of intercalation is significantly reduced, or even in the absence of myosin polarity. Conversely, mutant embryos that fail to achieve posterior midgut invagination, which was shown to pull on the germband, also fail to extend the germband, even though myosin polarity is preserved (Collinet et al., 2015). This suggests that intercalation – even active – might support extension rather than drive it. It seems that convergent extension, the alpha and omega of tissue morphogenesis, still holds mysteries for the years to come.

References

Article and author information

Author details

  1. Raphaël Clément

    Raphaël Clément is in the Institut de Biologie du Développement de Marseille, Aix Marseille University, CNRS, Marseille, France

    For correspondence
    raphael.clement@univ-amu.fr
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1270-1934

Publication history

  1. Version of Record published: May 3, 2024 (version 1)

Copyright

© 2024, Clément

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

Metrics

  • 338
    views
  • 39
    downloads
  • 0
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Raphaël Clément
(2024)
Morphogenesis: The enigma of cell intercalation
eLife 13:e98052.
https://doi.org/10.7554/eLife.98052
  1. Further reading

Further reading

    1. Developmental Biology
    Meng-Hao Pan, Kun-Huan Zhang ... Shao-Chen Sun
    Research Article

    During mammalian oocyte meiosis, spindle migration and asymmetric cytokinesis are unique steps for the successful polar body extrusion. The asymmetry defects of oocytes will lead to the failure of fertilization and embryo implantation. In present study, we reported that an actin nucleating factor Formin-like 2 (FMNL2) played critical roles in the regulation of spindle migration and organelle distribution in mouse and porcine oocytes. Our results showed that FMNL2 mainly localized at the oocyte cortex and periphery of spindle. Depletion of FMNL2 led to the failure of polar body extrusion and large polar bodies in oocytes. Live-cell imaging revealed that the spindle failed to migrate to the oocyte cortex, which caused polar body formation defects, and this might be due to the decreased polymerization of cytoplasmic actin by FMNL2 depletion in the oocytes of both mice and pigs. Furthermore, mass spectrometry analysis indicated that FMNL2 was associated with mitochondria and endoplasmic reticulum (ER)-related proteins, and FMNL2 depletion disrupted the function and distribution of mitochondria and ER, showing with decreased mitochondrial membrane potential and the occurrence of ER stress. Microinjecting Fmnl2-EGFP mRNA into FMNL2-depleted oocytes significantly rescued these defects. Thus, our results indicate that FMNL2 is essential for the actin assembly, which further involves into meiotic spindle migration and ER/mitochondria functions in mammalian oocytes.

    1. Chromosomes and Gene Expression
    2. Developmental Biology
    F Javier DeHaro-Arbona, Charalambos Roussos ... Sarah Bray
    Research Article

    Developmental programming involves the accurate conversion of signalling levels and dynamics to transcriptional outputs. The transcriptional relay in the Notch pathway relies on nuclear complexes containing the co-activator Mastermind (Mam). By tracking these complexes in real time, we reveal that they promote the formation of a dynamic transcription hub in Notch ON nuclei which concentrates key factors including the Mediator CDK module. The composition of the hub is labile and persists after Notch withdrawal conferring a memory that enables rapid reformation. Surprisingly, only a third of Notch ON hubs progress to a state with nascent transcription, which correlates with polymerase II and core Mediator recruitment. This probability is increased by a second signal. The discovery that target-gene transcription is probabilistic has far-reaching implications because it implies that stochastic differences in Notch pathway output can arise downstream of receptor activation.