▸ Research ⋯ Developmental Biophysics
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Vertebrate segmentation is driven by the so-called segmentation clock – a multi-cellular network of genetic oscillators. In zebrafish these cellular oscillators are mutually coupled via the intercellular Delta-Notch signaling pathway leading to synchrony among these oscillators. How this synchrony is established and how its loss determines the position of segmentation defects in Delta and Notch mutants was unknown.
In order to analyze the clock’s synchrony dynamics we developed a widely applicable experimental method for quantitative gene perturbation based on Morpholinos and the gamma-secretase inhibitor DAPT.
Using these inhibitors in a concentration dependent manner we generated fish that had their segmentation defects at specific postions (termed "Anterior Limit of Defect"="ALD")
Applying a physical theory of coupled phase oscillators we were able to account for thes ALD in a quantitative way, i.e. we related segmentation phenotype (ALD) to the coupling strength among cells due to Delta-Notch (inhibitor concentration).
Furthermore we showed experimentally that synchrony among genetic oscillators can be established by simultaneous gene induction and by self-organization.
This work led to a deeper understanding of the synchrony dynamics among coupled genetic oscillators. Furthermore we were able to quantify key parameters of the system such as the developmental noise, the coupling strength among genetic oscillators, mRNA decay rates, and the robustness of this system.