Perturbation analysis of a multi-morphogen Turing reaction-diffusion stripe patterning system reveals key regulatory interactions.

Andrew D Economou,Jeremy B A Green,Nicholas A M Monk

doi:10.1242/dev.190553

Andrew D Economou, Jeremy B A Green + Show 1 more

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https://doi.org/10.1242/dev.190553

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Abstract

ABSTRACTPeriodic patterning is widespread in development and can be modelled by reaction-diffusion (RD) processes. However, minimal two-component RD descriptions are vastly simpler than the multi-molecular events that actually occur and are often hard to relate to real interactions measured experimentally. Addressing these issues, we investigated the periodic striped patterning of the rugae (transverse ridges) in the mammalian oral palate, focusing on multiple previously implicated pathways: FGF, Hh, Wnt and BMP. For each, we experimentally identified spatial patterns of activity and distinct responses of the system to inhibition. Through numerical and analytical approaches, we were able to constrain substantially the number of network structures consistent with the data. Determination of the dynamics of pattern appearance further revealed its initiation by ‘activators’ FGF and Wnt, and ‘inhibitor’ Hh, whereas BMP and mesenchyme-specific-FGF signalling were incorporated once stripes were formed. This further limited the number of possible networks. Experimental constraint thus limited the number of possible minimal networks to 154, just 0.004% of the number of possible diffusion-driven instability networks. Together, these studies articulate the principles of multi-morphogen RD patterning and demonstrate the utility of perturbation analysis for constraining RD systems.This article has an associated ‘The people behind the papers’ interview.

Highlights

The generation of anatomy by self-organisation remains one of the most important subjects in the study of biology
Chemical inhibitors implicate FGF, hedgehog, Wnt and BMP pathways in periodic ruga patterning We previously showed that the periodic stripes of expression of the sonic hedgehog (Shh) gene in the mouse mid-gestation palate depend on the Hh pathway itself as an ‘inhibitor’ and the FGF pathway as an ‘activator’ (Economou et al, 2012)
We were deliberately agnostic about the specific FGF ligand-receptor pair that was crucial because multiple FGFs and FGF receptors are expressed in the palate (Porntaveetus et al, 2010)

Summary

Introduction

The generation of anatomy by self-organisation remains one of the most important subjects in the study of biology It has acquired new importance as a guiding feature of regenerative medicine and the modelling of disease processes by the creation of self-organising organoids from stem cells (Werner et al, 2017). In Turing’s initial formulation, an initially stable system of two or more interacting morphogens can be destabilised (i.e. generate nonuniform distributions) into a periodic pattern through diffusion (Turing, 1952). This is referred to as a diffusion-driven instability (DDI). Since the 1970s, numerous examples of RD behaviour have been described and analysed, and more recently the methods of molecular biology and biochemistry have identified a number of morphogen pairs, which are generally protein growth factors or growth-factor-binding proteins, that fit Turing’s and Meinhardt’s minimal description (e.g. Economou et al, 2012; Jung et al, 1998; Michon et al, 2008; Mou et al, 2006; Sick et al, 2006)

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