Assistant Professor, Mechanobiology Institute, National University of Singapore
+65 6601 1552 ext 11552
Level 9 T-Lab
National University of Singapore
5A Engineering Drive 1
Mechanics of Development Lab
Mechanotransduction in Tissues Group
Asst. Prof. Timothy Saunders, MBI Principal Investigator and Department of Biological Sciences, NUS has been selected to join the European Molecular Biology Organisation (EMBO) Global Investigator Network.
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Both when and where matter
How heart cells find their partners
My research tackles two major problems in developmental biology: (1) how do embryos ensure coordinated development to ensure robust morphogenesis?; (2) how does complex organ shape emerge during developing? We focus on using quantitative biology techniques and modelling to deepen our understanding of these important questions. We are particularly interested in the role of mechanical interactions in guiding morphogenesis, and how such mechanics interacts with signalling networks during development.
My lab also studies how complex three-dimensional tissue shape emerges. Using the developing Zebrafish myotome as a model system, we have utilized light-sheet microscopy to create a four-dimensional map of the developing myotome. The myotome has signalling inputs from three orthogonal morphogens (BMP, Shh, FGF), as well as considerable cellular rearrangement and shape change. Using our maps, we have found, for example, that FGF determines slow muscle fibre cell fate, not by direct signalling, but instead non-autonomously by regulating the elongation and migration of fast muscle cells which subsequently displace the slow muscle fibres from the source of Shh. Relatedly, we are exploring the biophysics of the emergence of the distinctive chevron shape of the myotome.
We have explored the role of differential mechanical interactions in the formation of the Drosophila heart. In particular, we have focused on the question of how cells of the same type reliably match during cardiogenesis. We have found that cell adhesion molecules Fasciclin-III and Teneurin-m act complementarily to provide an adhesion gradient across each heart segment, which results in reliable cell matching.
Developing organisms are three-dimensional, yet much research into tissue mechanics and interactions has focused on relatively flat tissues, such as the Drosophila wing disc. We are exploring how cells arrange and compete for space in curved three-dimensional environments. Using theory and experiment, we have shown that during cellularisation in the Drosophila embryo, cells undergo skew and apical-to-basal neighbour rearrangements to adapt for geometric constraints.
Finally, we are interested in organ scaling. Even between closely related animals there can be considerable variation in body size. Yet, for example, organs are typically positioned in the correct relative position for each specimen. Using light-sheet microscopy, we are using Drosophila embryogenesis to explore when and how such scaling decisions are made.
A developing organism needs to regulate the onset of different process temporally as well as spatially. Gene regulatory networks have been intensively studied in the Drosophila embryo, yet how networks temporal integrate input signals remains poorly understood. We developed an optogenetic tool that enabled us to spatially and temporally control the activity of a morphogen (Bicoid). We have determined the time windows for Bicoid activity and revealed spatial dependence in the timing of Bicoid readout, with more anterior genes requiring Bicoid input earlier and for longer than more posterior target genes.
How do embryos adapt to temporal variation–for example, due to environmental changes? We have shown that expression of specific microRNAs is variable at different temperatures within the Drosophila embryo, and this temperature-specific regulation plays a crucial role in ensuring robust development. Further, we have quantified temporal precision in development, and this work has revealed intriguing temperature-specific behaviour in the temporal development of Drosophila.
Signaling networks and morphogenesis
Position can be defined by the use of spatially extended gradients of signaling molecules. Since biological processes are inherently noisy, these gradients require mechanisms to ensure that they are precisely interpreted. We examine how the mechanisms of gradient formation affect the robustness of the downstream signaling. We have also explored how morphogens can be reliably interpreted prior to obtaining their steady-state profile.
We have modelled the role of morphogens in formation of eyespots in the butterfly wing. Our model can successfully replicate a wide range of mutant phenotypes from CRISPR-Cas9 mutations of the gene Distalless, providing insight into the emergence of complex traits.
As a next step, we want to combine our exciting results in organogenesis and morphogen gradient readout to better understand how complex shape emerges during development.
TOOLS AND METHODS
We use state-of-the-art light-sheet microscopy. This enables us to image entire developing organisms in toto while also having sufficient spatial and temporal resolution to probe single cell behavior.
The lab produces large amounts of quantitative data. We develop sophisticated methodologies to handle terabytes of data and extract the biological relevant information.
Mathematical modeling is used to make predictions about system behavior. Methods used include reaction-diffusion equations and Gillespie stochastic simulations. We are also interested in exploring how gene regulatory networks ensure robust decision-making.
2010 – 2013 EIPOD Fellow in the groups of Dr Lars Hufnagel and Dr Eileen Furlong at EMBL-Heidelberg, Germany
2007 – 2010 Postdoctoral researcher in the group of Professor Martin Howard at John Innes Centre, Norwich, UK
2007 PhD (Theoretical physics) University of Oxford
2004 MPhys 1st class, Cambridge University
2003 BA 1st class, Cambridge University
- Tlili S, Yin J, Rupprecht J, Mendieta-Serrano MA, Weissbart G, Verma N, Teng X, Toyama Y, Prost J, and Saunders TE. Shaping the zebrafish myotome by intertissue friction and active stress. Proc. Natl. Acad. Sci. U.S.A. 2019;. [PMID: 31772022]
- Connahs H, Tlili S, van Creij J, Loo TYJ, Banerjee TD, Saunders TE, and Monteiro A. Distal-less activates butterfly eyespots consistent with a reaction diffusion process. Development 2019;. [PMID: 30992277]
- Saunders TE, and Ingham PW. Open questions: how to get developmental biology into shape? BMC Biol. 2019; 17(1):17. [PMID: 30795745]
- Yin J, Lee R, Ono Y, Ingham PW, and Saunders TE. Spatiotemporal Coordination of FGF and Shh Signaling Underlies the Specification of Myoblasts in the Zebrafish Embryo. Dev. Cell 2018; 46(6):735-750.e4. [PMID: 30253169]
- Durrieu L, Kirrmaier D, Schneidt T, Kats I, Raghavan S, Hufnagel L, Saunders TE, and Knop M. Bicoid gradient formation mechanism and dynamics revealed by protein lifetime analysis. Mol. Syst. Biol. 2018; 14(9):e8355. [PMID: 30181144]
- Zhang S, Amourda C, Garfield D, and Saunders TE. Selective Filopodia Adhesion Ensures Robust Cell Matching in the Drosophila Heart. Dev. Cell 2018; 46(2):189-203.e4. [PMID: 30016621]
- Chong J, Amourda C, and Saunders TE. Temporal development of Drosophila embryos is highly robust across a wide temperature range. J R Soc Interface 2018; 15(144). [PMID: 29997261]
- Bauer G, Fakhri N, Kicheva A, Kondev J, Kruse K, Noji H, Riveline D, Saunders TE, Thattai M, and Wieschaus E. The Science of Living Matter for Tomorrow. Cell Syst 2018; 6(4):400-402. [PMID: 29698645]
- Saunders TE, He CY, Koehl P, Ong LLS, and So PTC. Eleven quick tips for running an interdisciplinary short course for new graduate students. PLoS Comput. Biol. 2018; 14(3):e1006039. [PMID: 29596417]
- Sun Z, Amourda C, Shagirov M, Hara Y, Saunders TE, and Toyama Y. Author Correction: Basolateral protrusion and apical contraction cooperatively drive Drosophila germ-band extension. Nat. Cell Biol. 2018;. [PMID: 29507405]