Modulation of Phase Shift between Wnt and Notch Signaling Oscillations Controls Mesoderm Segmentation

How signaling dynamics encode information is a central question in biology. During vertebrate development, dynamic Notch signaling oscillations control segmentation of the presomitic mesoderm (PSM). In mouse embryos, this molecular clock comprises signaling oscillations of several pathways, i.e., Notch, Wnt, and FGF signaling. Here, we directly address the role of the relative timing between Wnt and Notch signaling oscillations during PSM patterning. To this end, we developed a new experimental strategy using microfluidics-based entrainment that enables specific control of the rhythm of segmentation clock oscillations. Using this approach, we find that Wnt and Notch signaling are coupled at the level of their oscillation dynamics. Furthermore, we provide functional evidence that the oscillation phase shift between Wnt and Notch signaling is critical for PSM segmentation. Our work hence reveals that dynamic signaling, i.e., the relative timing between oscillatory signals, encodes essential information during multicellular development. [Display omitted] •Wnt and Notch signaling wave dynamics differ within segmenting mouse mesoderm•Entraining oscillations by microfluidics allows external control of the dynamics•Oscillatory Wnt and Notch signaling networks are coupled at the level of dynamics•Relative timing of Wnt and Notch signaling oscillations is critical for segmentation The relative timing between oscillatory Wnt and Notch signaling is critical for the segmentation of mouse embryo mesoderm.