Mechanism of oscillatory Wnt signaling dynamics and its role in vertebrate embryos
The aim of this project is to reveal the mechanism underlying Wnt signaling oscillations linked to the embryonic somite segmentation clock. Our strategy builds on combining real-time imaging quantifications of novel knock-in Wnt signaling reporter lines with time-resolved functional perturbations, using in vitro systems but importantly, also directly in developing mouse and medaka embryos. Specifically, we will investigate the role of candidate transcription factors Sp5 and Sp8, for which we have identified protein level oscillatory dynamics in an ES-cell derived in vitro model of cyto- clock oscillations. We will employ an auxin degron system that will allow depletion of Sp5/Sp8 proteins in a time-resolved manner and to quantify the immediate effects on Wnt signaling oscillation dynamics. In addition, we will make use of a synchronization theory-guided entrainment strategy that we have recently established in the lab. The entrainment approach offers unique possibilities to distinguish permissive from instructive roles and is hence uniquely suited to gain understanding into dynamic feedback regulation in complex, dynamical systems such as the somite segmentation clock. Finally, we will investigate the link between Wnt signaling dynamics and metabolic activity, specifically glycolysis. Our previous data indicates a functional link between Wnt and glycolytic activity and our goal within the CRC 1324 is to reveal the underlying mechanistic principles. This will enable to query the role of this newly identified link of metabolism to cellular signaling in other developmental systems and also in disease states.
- Sonnen, K.F., V.M. Lauschke, J. Uraji, H.J. Falk, Y. Petersen, M.C. Funk, M. Beaupeux, P. François, C.A. Merten, and A. Aulehla. 2018. Modulation of Phase Shift between Wnt and Notch Signaling Oscillations Controls Mesoderm Segmentation. Cell. 172:1079-1090.e1012.
- Bulusu, V., N. Prior, M.T. Snaebjornsson, A. Kuehne, K.F. Sonnen, J. Kress, F. Stein, C. Schultz, U. Sauer, and A. Aulehla. 2017. Spatiotemporal Analysis of a Glycolytic Activity Gradient Linked to Mouse Embryo Mesoderm Development. Dev Cell. 40:331-341 e334.
- Tsiairis, C.D., and A. Aulehla. 2016. Self-Organization of Embryonic Genetic Oscillators into Spatiotemporal Wave Patterns. Cell. 164:656-667.
- Lauschke, V.M., C.D. Tsiairis, P. Francois, and A. Aulehla. 2013. Scaling of embryonic patterning based on phase-gradient encoding. Nature. 493:101-105.