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3D Tissue elongation via ECM stiffness-cued junctional remodeling

Dong-Yuan Chen, Justin Crest, Sebastian J Streichan, David Bilder

Preprint posted on August 06, 2018 https://www.biorxiv.org/content/early/2018/08/06/384958

A mechanochemical pathway drives tissue elongation in edgeless epithelia.

Selected by Sundar Naganathan

Background

The Drosophila egg chamber or follicle transforms from a spherical shape to a tube-like ellipsoidal shape over several hours. The follicle and many other tubular organs are examples of edgeless epithelia. In the Drosophila egg chamber, it was previously shown that PCP signaling, which is known to drive elongation in multiple contexts during embryo development across species, plays a minimal role (Crest J. et al., 2017). Moreover, there is no evidence of myosin relocalization during follicle elongation. How do tubular organs such as the egg chamber elongate?

It was recently shown that the instructive cues arise from gradients in stiffness along the extracellular matrix (ECM) (Crest J. et al., 2017). In this model, a gradient of ECM stiffness provides differential resistance to luminal expansion, leading to tissue elongation. How do cells respond to this external stiffness gradient that ultimately drives tissue elongation? The authors uncover a mechanochemical signaling pathway that translates the external stiffness gradient into altered cadherin trafficking at adherens junctions, which facilitates tissue elongation.

Key findings

The authors imaged follicle morphogenesis from stage (st.) 4 to 8 of egg chamber development using confocal as well as light sheet microscopy and map projected the resulting 3D data onto a 2D surface. They first confirmed and quantified more accurately metrics of cell and tissue state properties over time, such as cell number, follicle volume, and apical and basal surface area. They then also characterized dynamic cellular behaviors accompanying follicle elongation and found that oriented cell divisions along the elongation axis as well as cell intercalations occurred. Moreover, a population of anterior cells aligned their cell elongation axis to that of the tissue during st.7-8, which is coincident with a period of post-mitotic tissue elongation.

To assess which of these cell behaviors play a major role in tissue elongation, the authors analyzed elongation in different mutants. Inhibition of mitosis did not lead to elongation defects, in spite of a reduced cell number. On the other hand, cell shape changes including a reorientation towards the AP axis (elongation axis) and cell intercalation from the equatorial to the AP axis seem to be important, as cadherin mutants (E-Cad) that affect these two quantities have tissue elongation defects.

Previously, it was shown that a graded ECM stiffness is important for follicle elongation. How is the external stiffness gradient coupled to cell reorientations and intercalations? From an ongoing RNAi screen in the lab, the authors selected Rack1, a scaffolding protein that maintains Src tyrosine kinase in an inactive state. Rack1 mutants have wild type-like graded stiffness but nevertheless display tissue elongation defects. Finally, by analyzing the phosphorylation status of Src and by performing FRAP experiments on GFP-tagged Ecad, the authors uncover a mechanotransduction pathway, whereby Src phosphorylation and thus its activity is coupled to the stiffness gradient of the ECM and affects Ecad trafficking to adherens junctions via Rack1. The dynamics of Ecad at the junctions affects cell reorientation and intercalation. The authors also discover that reorientation of anterior cells during st. 7-8 plays a major role in elongation, as local depletion of Rack1 in the anterior leads to severe tissue-scale elongation defects.

Why I chose this preprint?

It is an exciting time for developmental biology with advanced microscopy and image analysis algorithms facilitating a 3D analysis of developing tissues. The highlighted preprint adds weight to this statement by performing a global spatiotemporal analysis of follicle morphogenesis using advanced methodologies. Importantly, the quantitative analysis adds yet another feather to an increasing repertoire of developmental processes where mechanics and chemistry are coupled. This so-called mechanochemical coupling (Gross P. et al., 2017) seems to be at the forefront of emergence of shape and form during embryo development across diverse species. The preprint also uncovers distinct mechanisms by which edgeless epithelia such as Drosophila follicle and trachea undergo morphogenesis.

Open questions

It was discovered that the anterior follicle cells drive tissue-scale elongation by undergoing cell shape changes and by changing their orientation towards the elongation axis. This shows that a local change in cell orientation leads to a global change in tissue shape. Can reorientation be triggered in the posterior follicle cells leading to a similar morphogenesis of the egg chamber? On a related note, is the curvature of the pole important in transducing the mechanochemical effect? Finally, based on the reported experiments, it will be exciting to develop a continuum mechanochemical model to precisely describe elongation dynamics in edgeless epithelia.

References

  1. Crest J. et al., Organ sculpting by patterned extracellular matrix stiffness, eLife, 2017.
  2. Gross P. et al., How active mechanics and regulatory biochemistry combine to form patterns in development, Annu. Rev. Biophys., 2017.

Tags: map projection, mechanics, morphogenesis, spim

Posted on: 1st October 2018

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