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A non-cell autonomous actin redistribution enables isotropic retinal growth

Marija Matejcic, Guillaume Salbreux, Caren Norden

Preprint posted on April 03, 2018 https://www.biorxiv.org/content/early/2018/04/03/293951

What are the cellular basis of isotropic organ growth? A recent preprint shows that global cell elongation, actin redistribution and cell proliferation underlie isotropic tissue growth of the zebrafish retinal neuroepithelium during development.

Selected by Yara E. Sánchez Corrales

Background

Some organs acquire their characteristic shape early in development and subsequently increase in size. However, the cellular basis for achieving isotropic tissue growth has been poorly explored. In this preprint, the authors investigate this problem by following tissue and cell dynamics during the development of the zebrafish retinal neuroepithelium (Figure 1a). This tissue acquires its characteristic shape early in development and grows isotropically afterwards. Matejcic et al. find that global cell elongation and actin redistribution enables tissue isotropic growth.

Key findings

The authors perform live-imaging to quantitatively asses the changes occurring at the cell and tissue-level during isotropic growth. During the tracked period, the tissue concurrently increases in thickness and area, allowing the tissue to preserve a constant aspect ratio (Figure 1b). In contrast, individual cells show marked apico-basal elongation and dramatic changes to their shape (Figure 1b). Cells also divide homogeneously within the tissue and decrease their volume exponentially.

What could underlie an isotropic 3D tissue growth? The authors propose two factors: actin redistribution and continued proliferation.

Actin shows a dynamic pattern of expression during isotropic growth. It accumulates basolaterally during early stages and later relocates to apical and basal positions (Figure 1c). Interestingly, this change in actin localisation within the cells correlated with an increase in cell elongation. Moreover, in a mutant (hdac1 -/-) in which actin redistribution is abrogated, cells did not elongate and the whole shape of the organ was disrupted. Thus, the authors suggest that the change of actin localisation could alter the mechanical properties of the cells, favouring a contraction apically and basally and expanding the lateral surface (Figure1 d-e).

However, when actin is depleted prematurely from the lateral sides, the tissue does not increase its height, suggesting that actin is necessary but not sufficient for triggering cell elongation and that additional factors contribute to tissue shape change. The authors propose that another important factor is a continued cell proliferation. Blocking proliferation caused no change in tissue height compared to wild type even when actin redistributed from lateral to basal locations.

Interestingly, a mechanical model taking into account the change in cell properties due to actin redistribution and a shift in differentiation is able to recapitulate the dynamics of cell volume, height and tissue area change observed from time-lapse experiments (Figure1 d-e).

Figure 1. (a) Isotropic growth of retinal neuroepithelium during development. (b) The tissue conserves a constant shape while the cells elongate and increase their aspect ratio over time. (c-c’) Actin redistributes from the lateral to apical and basal sides of the cells. (d) and (e) Summary of the model that takes into account the change in cell properties due to actin redistribution and change in differentiation programs. Panel a and b correspond to Figure 1; panel c corresponds to Figure 3 and panel d and e correspond to Figure 4 of the original preprint.

What I like about this preprint and open questions

Anisotropic cell shape changes, with a particular direction and strength, are often associated with anisotropic tissue change. One of the results I found more interesting in this preprint is that anisotropic changes at the cell-level underlie isotropic changes at the the tissue-level. In my opinion, this highlights the importance of quantitative analysis and dynamic measurements to understand different growth regimes.

I think this preprint is very interesting because it explores the 3D cell dynamics in the context of a developing organ. A lot of our knowledge on cell behaviours has been built focusing on the apical side of the cells, thus ignoring cell behaviours that emerge as 3D properties. For instance, cell elongation, as discussed in this preprint, is an important factor enabling isotropic growth.

I also like this work because it is a beautiful example of the multi-scale nature of morphogenesis. The coordinated changes in cell properties (due to a dynamic expression pattern of actin) can lead to global changes at the level of the tissue. Thus, in my opinion, to fully understand tissue shape change, we need to study dynamically different levels of organisation.

An open question is what drives the coordinated apico-basal cell elongation. Since it is a global change and it is non-cell autonomous, an interesting proposal is that a global cue (perhaps Wnt or Notch) could underlie this dynamic pattern of cell shape change and would be a very interesting aspect to explore in the future.

Another interesting question is the role of the extracellular matrix (ECM). The authors provide a theoretical framework that includes the transition in cell properties and the shift in cell differentiation. I wonder whether the influence of the ECM could be integrated in their model and whether this could have an effect on the temporal dynamics of their simulations.

Tags: cell dynamics, growth, quantitative

Posted on: 30th May 2018

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  • Author's response

    Marija Matejcic shared

    I really liked your points and the enthusiasm about the complexity of development you bring across. I think the points you make about the multi-scale, 3D analysis are very important. Also, we hope that highly quantitative approaches can become a standard in developmental biology. Such approaches can easily strengthen or identify problems with conclusions of a study, allow higher reproducibility, and in general allow better understanding of a developing system.
    As a side note about isotropic growth, personally, I am surprised at how easily developmental biologists (including myself) take isotropic growth for granted. I guess it seems to us as very simple task: it looks complicated to establish the shape during development, but then the system “just” needs to maintain it. With this study, we wanted to draw attention to the fact that it’s not all that trivial. Who knows how many other developmental processes we are missing because we don’t see them as challenging or complex enough tasks for the developing system.

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