During embryogenesis, the formation of complex tissues and organs are usually driven by remodeling of epithelial cells. Epithelial morphogenesis is an intrinsically mechanical process dictated by forces and the mechanical properties of tissues. Despite significant progress in deciphering the genetic and biochemical determinants of force generation, little is known about how tissue mechanical properties are regulated and how this regulation contributes to morphogenesis. Using Drosophila gastrulation as a model, our recent work reveals that the collective cell shape changes underlying apical constriction-mediated mesoderm invagination are dictated by region-specific mechanical properties of the tissue. The tissue interior behaves as a viscous continuum and flows as the cells constrict apically, thereby mediating the apical- basal lengthening of the cells. In contrast, the subsequent tissue invagination is contingent on the rigidity of the apical surface of the flanking, non-constricting cells. The mechanical properties inherent to the tissue interior and surface are controlled by proteins that regulate cell membrane expansion and cell polarity, respectively. Disruption of these proteins affects specific aspects of tissue folding. In the proposed study, we will use a multipronged approach combining genetics, quantitative live-imaging, biophysics and computer modeling to (1) identify the cellular mechanisms that facilitate viscous deformation of cells in the tissue interior and (2) determine how the rigidity of the tissue surface is regulated and how flanking cells contribute to tissue invagination. To facilitate our work, we have developed biophysical approaches to probe tissue mechanical properties in vivo and optogenetic tools to control protein activities with high spatiotemporal precision. Successful completion of our research goals will advance scientific knowledge by identifying cellular mechanisms that define region-specific mechanical properties and pinpointing their role in coherent tissue deformation. Moreover, our findings will shed light on the fundamental regulatory networks that govern how tissues sense and respond to mechanical forces underlying a variety of developmental and physiological processes.

Public Health Relevance

The folding of 2-dimensional epithelial sheets into multilayered tissues provides a key strategy to shape tissues during embryogenesis. We use the model organism the fruit fly Drosophila melanogaster to determine the molecular and mechanical mechanisms of epithelial folding. Our findings will be critical to understanding how epithelial cells integrate various developmental signals to form complex tissue and organ structures and how defects in this process result in embryonic lethality and congenital birth defects.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZGM1)
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Hoodbhoy, Tanya
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Dartmouth College
Schools of Arts and Sciences
United States
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