Excitable Dynamics and Yap-Dependent Mechanical Cues Drive the Segmentation Clock

Abstract

SUMMARY The periodic segmentation of the vertebrate body axis into somites, and later vertebrae, relies on a genetic oscillator (the segmentation clock) driving the rhythmic activity of signaling pathways in the presomitic mesoderm (PSM). To understand whether oscillations are an intrinsic property of individual cells or represent a population-level phenomenon, we established culture conditions for stable oscillations at the cellular level. This system was used to demonstrate that oscillations are a collective property of PSM cells which can be actively triggered in vitro by a dynamical quorum sensing signal involving Yap and Notch signaling. Manipulation of Yap-dependent mechanical cues is sufficient to predictably switch isolated PSM cells from a quiescent to an oscillatory state in vitro, a behavior reminiscent of excitability in other systems. Together, our work argues that the segmentation clock behaves as an excitable system, introducing a broader paradigm to study such dynamics in vertebrate morphogenesis.

A sense of place, many times over ‐ pattern formation and evolution of repetitive morphological structures

“…Here, the development of dedicated ex vivo and/or in vitro models might prove invaluable to study a given patterning module in true isolation. This has already successfully been realized for important aspects of somitogenesis, or in different organoid systems . In combination with microfluidic or optogenetic approaches controlling morphogen signaling, such ex vivo/in vitro methods are likely to contribute to a more quantitative understanding of the underlying molecular and cellular processes .…”

“…This has already successfully been realized for important aspects of somitogenesis, or in different organoid systems. 31,109,143,144 In combination with microfluidic or optogenetic approaches controlling morphogen signaling, such ex vivo/in vitro methods are likely to contribute to a more quantitative understanding of the underlying molecular and cellular processes. 133,145,146 Furthermore, emerging techniques to measure and perturb various intrinsic parameters with cellular resolution will help to disentangle how virtually homogenous, extracellular positional information can be interpreted differentially cell-intrinsically, to result in discretized cellular states.…”

“…The development of models that are able to approximate important aspects of somite segmentation ex vivo, in vitro and/or in silico have empowered experimental and theoretical approaches to study the process at a more quantitative level. Many of them focus on some of the apparent self‐organizing properties of the process, in particular for size scaling and the emergence of the molecular oscillator . Some iterations abandon the notion of the importance of global positional information via gradients altogether, in favor of an oscillatory reaction–diffusion mechanism .…”

“…Many of them focus on some of the apparent self-organizing properties of the process, in particular for size scaling and the emergence of the molecular oscillator. 30,31,[108][109][110][111] Some iterations abandon the notion of the importance of global positional information via gradients altogether, in favor of an oscillatory reaction-diffusion mechanism. 112 Importantly, however, only by explicitly including termination of elongation and patterning in these models will the true evolutionary diversity in vertebral formulas be accounted for.…”

CDK 1 and CDK 2 regulate NICD 1 turnover and the periodicity of the segmentation clock

“…Synchronization of clock gene oscillations between neighbouring cells is reliant on Notch signalling [10][11][12][13]. Synchronization of clock gene oscillations between neighbouring cells is reliant on Notch signalling [10][11][12][13].…”