Biology subjects

Economou, A. D.

Publications and source records attributed to Economou, A. D..

3 recordsLinked to original sources

bioRxiv2022

Nodal signaling establishes a competency window for stochastic cell fate switching

Specification of the germ layers by Nodal signaling has long been regarded as an archetype of how graded morphogens induce different cell fates. However, this deterministic model cannot explain why only a subset of cells at the margin of the early zebrafish embryo adopt the endodermal fate, while their immediate neighbours, experiencing similar signaling profiles, become mesoderm. Combining pharmacology, quantitative imaging and single cell transcriptomics, we demonstrate that sustained Nodal signaling establishes a bipotential progenitor state where cells initially fated to become mesoderm can switch to an endodermal fate. Switching is a random event, the likelihood of which is modulated by Fgf signaling. This inherently imprecise mechanism nevertheless leads to robust endoderm formation because of buffering at later stages. Thus, in contrast to previous deterministic models of morphogen action, Nodal establishes a temporal window when cells are competent to undergo a stochastic cell fate switch, rather than determining fate itself.

developmental biology↗

bioRxiv2019

Perturbation analysis of a multi-morphogen Turing Reaction-Diffusion stripe patterning system reveals key regulatory interactions

Periodic patterning is extremely widespread in developmental biology and is broadly modelled by Reaction-Diffusion (RD) processes. However, the minimal two-component RD system is vastly simpler than the multimolecular events that current biology is now able to describe. Moreover, RD models are typically underconstrained such that it is often hard to meaningfully relate the model architecture to real interactions measured experimentally. To address both these issues, we investigated the periodic striped patterning of the rugae (transverse ridges) in the roof of the mammalian palate. We experimentally implicated a small number of major signalling pathways and established theoretical limits on the number of pathway network topologies that can account for the stable spatial phase relationships of their observed signalling outputs. We further conducted perturbation analysis both experimentally and in silico, critically to assess the effects of perturbations on established patterns. We arrived at a relatively highly-constrained number of possible networks and found that these share some common motifs. Finally, we examined the dynamics of pattern appearance and discovered a core network consisting of epithelium-specific FGF and Wnt as mutually antagonistic "activators" and Shh as the "inhibitor", which initiates the periodicity and whose existence constrains the network topology still further. Together these studies articulate the principles of multi-morphogen RD patterning and demonstrate the utility of perturbation analysis as a tool for constraining networks in this and, in principle, any RD system.

developmental biology↗

bioRxiv2019

Epithelial invagination by vertical telescoping

Epithelial bending is a fundamental process that shapes organs during development. All currently known mechanisms involve cells locally changing shape from columnar to wedge-shaped. Often this shape change occurs by cytoskeletal contraction at cell apices (\"apical constriction\") but mechanisms such as basal nuclear positioning (\"basal wedging\") or extrinsic compression are also known. Here we demonstrate a completely different mechanism which occurs without cell wedging. In mammalian salivary glands and teeth, we show that initial invagination occurs through coordinated vertical cell movement. Specifically, we show that cells towards the periphery of the placode move vertically upwards while their more central neighbours move downwards to create the invagination. We further show that this occurs by active cell-on-cell migration: outer cells migrate with an apical leading edge protrusion, depressing the central cells to \"telescope\" the epithelium downwards into the underlaying mesenchyme. Cells remain basally attached to the underlying lamina while their apical protrusions are dynamic and planar polarised centripetally. These protrusions depend on the actin cytoskeleton, and inhibition of the branching molecule Arp2/3 inhibits them and the invagination. FGF and Hedgehog morphogen signals are also required, with FGF providing a directional cue. These findings show that epithelial bending can be achieved by novel morphogenetic mechanism of coordinated cell rearrangement quite distinct from previously recognised invagination processes.

developmental biology↗