The form that organs acquire during development is critical for their functionality.Forexample,failedtissue loopingduringheartdevelopmentresultsincongenitalheartdisease-themostcommonbirthdefectobserved inhumans.While many studies have identified how cells are fated to perform their tasks, we know little about the forces that shape tissues. Transcription factors (TFs) spanning multiple length scales - ranging from a few to hundreds of cells - precisely regulate gene expression programs. These programs generate the physical stresses that give rise to cell behavior. To ensure that organs take on their proper shape vital for their function, physical stresses must be coordinated across tissues spanning multiple length scales. We are beginning to understand how short-ranged TFs control physical stresses at the level of individual cells. This proposal seeks to uncover how tissues are shaped by physical stresses, controlled at the organ scale, using D. melanogaster as a model system. Novel methods for in toto live imaging and tissue cartography have revealed: cell behavior is modulated along the dorsoventral (DV) axis during germband extension. DV behavior modulation is lost in dorsalizing mutants. These findings challenge the assumption, that long-range TFs, such as Dorsal, act only indirectly by setting up short-range patterns to control stress. To test the hypothesis that long-range TFs modulate physical stresses responsible for organ shape, we propose:
Aim 1 to measure physical stress at the organ scale, and by systematic comparison to known TF expression patterns, identify the role of Dorsal in organ scale stress coordination.
In aim 2 we will extend our observations to investigate coordination of cell behavior across heterologous tissue layers during midgut looping. The proposed research combines quantitative experiments with theory, to provide the first strategy for measuring TF mediated global stress coordination that shapes organs. State of the art microscopes and tools designed for analyzing cell behaviors that produce complex shapes will open new opportunities for understanding how intricate organs form, including loops.
Organfunctionalityrequiresexquisitelycontrolledforcesthatshapetissuesduringanimaldevelopment.This studywillanalyzenovelmodesofforcecoordinationattheorganscalespanning100sofcells,andlaythe foundationfortissueengineering.
| Streichan, Sebastian J; Lefebvre, Matthew F; Noll, Nicholas et al. (2018) Global morphogenetic flow is accurately predicted by the spatial distribution of myosin motors. Elife 7: |
| Noll, Nicholas; Mani, Madhav; Heemskerk, Idse et al. (2017) Active Tension Network model suggests an exotic mechanical state realized in epithelial tissues. Nat Phys 13:1221-1226 |
| Heemskerk, Idse; Streichan, Sebastian J (2015) Tissue cartography: compressing bio-image data by dimensional reduction. Nat Methods 12:1139-42 |
