Coordinated growth of linked epithelia is mediated by the Hippo pathway

Sophia Friesen, Iswar K. Hariharan

Posted on: 6 March 2023

Preprint posted on 26 February 2023

Roses are red, violets are blue, when the disk proper grows, hippo stretches peripodial epithelium too.

Selected by Girish Kale

Categories: cell biology, developmental biology

Background:

The journey of life starts as a single cell, growing into a multicellular individual over time. In this span of time, specialised structures, like tissues and organs, grow in a coordinated manner. Here, coordination doesn’t necessarily mean that the growth is uniform. For instance, the head-to-body ratio is larger in babies than in adults, illustrating that different parts of the body will grow at different rates and body proportions keep changing over time. Despite this, overall body growth remains left-right symmetric. How such growth coordination is achieved is a fascinating question, one that many researchers are working on.

In general, growth coordination can be studied at two levels: 1) coordination at the scale of entire organism and 2) coordination between neighbouring organs/tissues. The latter is the focus of this preprint. As we can probably all imagine, local growth coordination is very important. For instance, think of what would happen if the skull doesn’t expand to allow the growth of the brain inside, or how the growth of the fetus will be hindered if the belly doesn’t expand during pregnancy. Researchers use various experimental model systems to answer questions related to local growth coordination. In case of this preprint, the authors study the wing imaginal disk, a structure that eventually gives rise to the wing of the fruit fly Drosophila melanogaster. Here, this disk has two tissues – the disk proper (DP) and the peripodial epithelium (PE) – that are connected to each other at the margins, and are known to grow in a coordinated manner. This is an ideal model system to study local growth coordination also due to the added advantage of being able to easily introduce genetic manipulations.

Key findings:

As discussed by the authors at the beginning of the preprint, a local coordination between neighboring tissues can be achieved via different mechanisms. We might have a scenario where, say, a growth hormone acts as a common regulator to simultaneously instruct the growth of both neighboring tissues, and coordinate the growth rates of the two tissues. Alternatively, the tissues might “communicate” with each other and directly regulate each other’s growth. It is also possible to have a “leader and follower” scenario, where the “follower” tissue essentially matches the growth of the “leader”. So, what’s happening in the case of the wing imaginal disk?

The two tissues, DP and PE, are attached at their margins, and thus “know” the growth rate of the other. In this preprint, the authors first independently manipulated the growth of the two tissues: thanks to the exquisite genetic toggles made possible by knowing “what makes a tissue tick”. Using the strength of fly genetics, the authors could first show that here we have a clear leader-follower scenario: DP is the leader, and PE the follower.

Having established the leader-follower dynamics between the two tissues, the authors then asked how exactly these tissues regulate their growth, and how DP instructs the growth in PE. Again, there are multiple possibilities as the two tissues are known to use similar signaling, akin to having a similar response to a common growth hormone. The authors first demonstrated, however, that, contrary to prior expectations, the response of these tissues to signaling is not the same. As such, the structure of the tissues is not comparable either: being connected at the tissue margins, they have a similar area, though DP has tall columnar cells, while PE has flat squamous cells. Also, the growth in DP occurs mainly by adding more cells, while that in PE occurs mainly through cell flattening, indicating that DP might be stretching PE. Thus, the authors asked whether PE has a specific ability to respond to tissue external stretch and looked specifically at the possible involvement of the ‘Hippo’ pathway.

The Hippo pathway gets its name from its main signalling component, the gene hippo, which in turn is named after the overgrowth-effect (hippopotamus-like phenotype) in the absence of hippo function. Interestingly, the authors found that Hippo signalling is important for PE cells to become squamous, and to respond to the stretching due to the growth in DP. This demonstrates an interesting component in tissue growth regulation, namely the tissue’s mechanical environment.

Importance of the findings:

This work will further the development of the conceptual framework to study local growth coordination. A better understanding of local coordination could also allow us to understand how local and global factors work together to regulate growth coordination. At the same time, the study also furthers our understanding of how tissue growth might be regulated by its local micro-environment: a key consideration in tumor biology, as it could be a path to identify new therapeutic targets. The study further demonstrates a role for Hippo pathway in normal development, which, according to the authors, has been bit of a contentious issue in the field.

Questions to authors:

1) What could be the future directions for the study? Will it be interesting to test if similar interactions also take place in other imaginal discs?

2) How does the local and global regulation of tissue growth interact with each other? The left and right DP presumably coordinate their growth. What will happen if this bilateral symmetry is challenged? Would we see an indirect effect on the growth rate of left or right PE, due to a respective change in growth rate of the right or left DP?

3) The “why” question: Do we know why the growth in PE follows that in DP? Structurally, the combination of DP and PE is reminiscent of the extra-embryonic tissues and embryo proper, and the ‘leader-follower’ dynamics will make sense if the PE had a supportive role for the growth and integrity of DP. What are your thoughts on this?

Tags: drosophila melanogaster, hippo pathway, mechanosensitive signalling, tissue growth coordination, wing imaginal disk

doi: https://doi.org/10.1242/prelights.34010

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Author's response

Sophia Friesen shared

1) I’m very interested in the possibility that stretch-induced growth, mediated by the Hippo pathway, could be a generalizable mechanism for tissues to coordinate their growth. Other researchers have observed similar results in another flat, squamous cell population that surrounds the Drosophila egg follicle (Fletcher et al. 2018), and the Hippo pathway is regulated by mechanical forces across a wide variety of contexts (reviewed in Chang et al. 2020). As a mechanosensitive pathway conserved between flies and vertebrates, the Hippo pathway could potentially coordinate developmental growth across diverse biological contexts. Zooming back in to this study, one intriguing future direction is finding the specific factors downstream of the Hippo pathway that cause the dramatic cell shape changes we see.

2) This is a fascinating question, and one that’s particularly tough to answer due to the difficulty of manipulating growth on only one side of the embryo. If the PE is truly matching growth of the DP due to mechanical stretching, as our results support, then I would expect the PE to remain proportional to the DP of the same wing disc, regardless of the size of the other wing disc.

3) I’m a little hesitant to answer “why” questions, because evolution doesn’t have a motive, but I can make some guesses as to how the leader-follower relationship we see could be advantageous. First of all, the parallel to extraembryonic tissues is a compelling one. The extraembryonic amnioserosa tissue of Drosophila embryos, like the PE, is a beautiful squamous tissue that supports the movement of adjacent epithelia during development. We know that the PE is involved in the dramatic morphological changes that the wing disc goes through during metamorphosis (Milner et al. 1984, Pastor-Pareja et al. 2004, Kosakamoto et al. 2018), so it would make sense that it has to maintain some degree of proportionality to the DP to properly mediate those changes. Experiments where the PE is surgically removed, or is converted to a duplicate DP, impair the development and growth of the DP (Gibson & Schubiger 2000, Nusinow et al. 2008), supporting the idea that the PE is required for DP development.

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Coordinated growth of linked epithelia is mediated by the Hippo pathway

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