Abstract
Integrity of rhythmic spatial gene expression patterns in the vertebrate segmentation clock requires local synchronization between neighboring cells by Delta-Notch signaling and its inhibition causes defective segment boundaries. Whether deformation of the oscillating tissue complements local synchronization during patterning and segment formation is not understood. We combine theory and experiment to investigate this question in the zebrafish segmentation clock. We remove a Notch inhibitor, allowing resynchronization, and analyze embryonic segment recovery. We observe unexpected intermingling of normal and defective segments, and capture this with a new model combining coupled oscillators and tissue mechanics. Intermingled segments are explained in the theory by advection of persistent phase vortices of oscillators. Experimentally observed changes in recovery patterns are predicted in the theory by temporal changes in tissue length and cell advection pattern. Thus, segmental pattern recovery occurs at two length and time scales: rapid local synchronization between neighboring cells, and the slower transport of the resulting patterns across the tissue through morphogenesis.
Highlights
Synchronization of genetic oscillations in tissues generates robust biological clocks
A critical prediction of these theories is that once a population of oscillators is synchronized, a large fluctuation of synchrony level is not expected (Hildebrand et al, 2007; Kuramoto and Nishikawa, 1987; Daido, 1987). Instead of such global phase order fluctuations, other hypotheses for the intermingled defects are the emergence of localized disorder, or the existence of local phase order with a mis-orientation to the global pattern. To explore these potential behaviors, following the general lineage of the clock and wavefront (Cooke and Zeeman, 1976), we develop a physical model of the presomitic mesoderm (PSM) and tailbud that brings together in a novel framework previous descriptions of (i) the local processes of phase coupling (Morelli et al, 2009) and physical forces (Uriu et al, 2017; Uriu and Morelli, 2014) between neighboring oscillators, and (ii) the tissue-level properties of a frequency profile and oscillator arrest front (Jorg et al, 2015; Morelli et al, 2009), changing tissue length (Jorg et al, 2015), and a gradient of cell mixing (Uriu et al, 2017); we introduce an advection pattern of the PSM (Jorg et al, 2015) that changes in time, Figure 2, Figure 2—figure supplement 1 and Supplementary file 1
Dependence of first recovered segment (FRS) and posterior limit of defects (PLD) on each tissue parameter. These results show that the model captures the intermingling of normal and defective boundaries frequently observed in the early washout experiments, but can the model capture the axial distribution of FRS and PLD observed in the late washout experiments, thereby joining these observations into a coherent picture of resynchronization across developmental stages?
Summary
Synchronization of genetic oscillations in tissues generates robust biological clocks. Cells interact with each other locally and adjust their phase of oscillations. How local interactions between oscillators lead to the emergence of collective rhythms has been studied in static tissues and in dynamic tissues with local cell rearrangements, but how collective rhythms are influenced by the more complex deformations of entire tissues typical in embryogenesis remains challenging and is less well understood. A system to explore this is the synchronization of genetic oscillations during the segmentation of the vertebrate embryo’s body axis, a process termed somitogenesis. Cells in the unsegmented tissue, namely the presomitic mesoderm (PSM) and the tailbud, show collective rhythms of gene expression that set the timing of somite boundary formation and are referred to as the segmentation clock (Oates et al, 2012; Pourquie, 2011).
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