Highlighted as one of Royal Society Open Biology's most popular articles this year, the team reveals how transient manipulation of a key developmental signalling pathway - sonic hedgehog (Shh) - can induce a dramatic shift from chemical pattern formation to mechanical skin folding in developing chicken embryos.
In their study, Rory Cooper, Ebrahim Jahanbakhsh, Gabriel Santos Durán, and Michel Milinkovitch from the Department of Genetics and Evolution at the University of Geneva (Switzerland), explore the remarkable interplay between chemical and mechanical processes that shape embryonic skin appendages. Their multidisciplinary approach, employing pharmacological manipulations, advanced microscopy, mechanical measurements, and computational simulations, offers exciting insights into the fundamental principles that guide biological form and patterning across diverse organisms. We asked lead author Michel Milinkovitch more about their work.
What first got you and your colleagues interested in how patterns, like scales or feathers, form during embryo development?
For quite some years, one focus of research in my laboratory has been the patterning of the skin, both in terms of skin colour and skin appendages. Our previous research explored reaction-diffusion (RD, or Turing patterns) and their role in skin colour patterning [2], as well as how these chemical patterns interact with skin geometry to generate complex cellular-automaton and Ising dynamics [3-7]. We have also examined the mechanical processes of skin folding in various species, from crocodiles to tortoises [8-10]. Investigating how both chemical and mechanical self-organisation contribute to structures like scales and feathers naturally aligned with my long-standing research interests.
Image: Michel Milinkovitch & Rory Cooper, Laboratory of Artificial & Natural Evolution (LANE), University of Geneva
What surprised you most in this study? Was there a moment when something clicked or changed how you thought about skin patterning?
It was a fantastic surprise to see that we could trigger in chickens a transition from RD patterning to mechanical folding! Indeed, scales typically are placode-derived developmental units that are chemically self-organised through Alan Turing’s RD mechanism [11,12]. However, we have shown that scales develop in a completely different way on the face and jaws of crocodilians [8,10], as well as on the top of the head of tortoises [9]: these scales self-organise through compressive skin folding. In other words, these scales are not developmental units (they do not form from placodes) and are instead random polygonal pieces of skin with a shape and size that depend on how the skin folds propagated and joined during embryonic development. What is very exciting in our Open Biology paper is that a transient over-activation of the Sonic Hedgehog (Shh) signalling pathway in chickens abolishes the Turing-like chemical patterning of reticulate scales on the ventral footpad and promotes a transition to mechanical labyrinthine skin folding. This spectacular result shows, for the first time, that the developmental and evolutionary transition between these two very different patterning mechanisms might be much easier than anticipated. Notably injecting the Shh agonist one day earlier (on the 11th day instead of the 12th day post egg-laying) does not abolish the RD patterning but permanently transforms each reticulate scale into… a feather [13].
Image: Normal development of avian skin appendages – taken from Figure 1 Open Biol.15240342 [1]
Do these findings have potential beyond chickens - for example, in understanding how human organs or skin develop, or even in designing materials or soft robotics?
Yes, the implications go far beyond the development of chicken foot scales. Our study demonstrates that perturbing gene regulatory networks can lead tissues to adopt entirely different developmental paths, which could significantly inform our understanding of human organ development and inspire novel approaches in materials science and soft robotics.
You use a variety of experimental approaches, from in ovo pharmacological manipulation to light sheet microscopy and PDMS simulations. Were there any challenges involved in bringing all these methods together?
We had recently established precise in-ovo injections of drugs [14] in both chicken [13] and crocodiles [10]. This facilitated our new study published in Open Biology. We also had already established light sheet microscopy on large samples [15,16], made PDMS experiments and mechanical simulation models of biological hyperelastic material [10,16,17]. This multidisciplinary mix of molecular developmental biology, physics of biology experiments and computer simulations is our signature approach.
What’s next for you or your group’s research? Where would you like to see research in the field heading?
Now, I am investigating how chemical and mechanical patterning mechanisms interact dynamically throughout development to generate the staggering diversity and complexity of morphologies we see in living and extinct species.
Image: Members of the Laboratory of Artificial & Natural Evolution (LANE), University of Geneva
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Main image credits: Michel Milinkovitch, Fabrice Berger & Rory Cooper.
References
[1] https://royalsocietypublishing.org/doi/10.1098/rsob.240342
[2] https://www.annualreviews.org/content/journals/10.1146/annurev-cellbio-120319-024414
[3] https://www.nature.com/articles/nature22031
[4] https://www.nature.com/articles/s41467-021-22525-1
[5] https://www.sciencedirect.com/science/article/pii/S096098222201692X
[6] https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.128.048102
[7] https://journals.aps.org/prx/abstract/10.1103/PhysRevX.13.041011
[8] https://www.science.org/doi/10.1126/science.1226265
[9] https://www.cell.com/iscience/fulltext/S2589-0042(25)00945-9
[10] https://www.nature.com/articles/s41586-024-08268-1
[11] https://www.science.org/doi/10.1126/sciadv.1600708
[12] https://www.science.org/doi/10.1126/sciadv.adf8834
[13] https://www.science.org/doi/10.1126/sciadv.adg9619
[14] https://www.sciencedirect.com/science/article/pii/S2666166723002915
[15] https://www.sciencedirect.com/science/article/pii/S2589004223005291
[16] https://www.cell.com/current-biology/fulltext/S0960-9822(24)01296-X
[17] https://elifesciences.org/articles/44455
