We propose to combine computational and experimental approaches to investigate the mechanisms of epithelial morphogenesis, defined as the set of processes that transform sheets of cells into three-dimensional (3d) structures of tissues and organs. Studies of epithelial morphogenesis are important for understanding of normal development and for elucidating the origins of developmental abnormalities, such as neural tube defects. We will focus on a type of epithelial morphogenesis that involves only cell shape changes and rearrangements and does not depend on cell divisions or death. Among the examples of this type of morphogenesis are the early stages of heart development in fish, the formation of optic cups in birds, and mesoderm invagination in insects. In our experimental system (Drosophila oogenesis), a sheet of nondividing cells gives rise to an elaborate 3d shape. This transformation is induced by well-understood chemical signals, which specify a fate map, a correspondence between positions of cells within the sheet and their ultimate positions within the 3d structure. Our goal is to understand how the two-dimensional (2d) fate map is transformed into a 3d structure. Answering this question is important in multiple developmental systems, from simple metazoans to humans. Our hypothesis is that 3d epithelial morphogenesis during Drosophila oogenesis is driven by the 2d distribution of mechanical tensions within the patterned cell sheet. We will test this hypothesis by computational modeling and live imaging of epithelial dynamics and by direct analysis of mechanical tensions in patterned epithelial sheets. Our work will lead to an experimentally validated computational framework for 3d epithelial morphogenesis. Given the highly conserved nature of processes involved in epithelial morphogenesis, the results of or studies may shed light on epithelial dynamics in wide range of developmental systems.

Public Health Relevance

We propose computational and experimental studies of epithelial morphogenesis, defined as the set of processes that convert two-dimensional sheets of cells into complex three-dimensional structures of tissues and organs. Studies of epithelial morphogenesis are important for mechanistic understanding of normal development and for elucidating the origins of developmental disorders.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01GM107103-01A1
Application #
8695795
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Lyster, Peter
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Princeton University
Department
None
Type
Organized Research Units
DUNS #
City
Princeton
State
NJ
Country
United States
Zip Code
08543
Du, XinXin; Osterfield, Miriam; Shvartsman, Stanislav Y (2014) Computational analysis of three-dimensional epithelial morphogenesis using vertex models. Phys Biol 11:066007
Fletcher, Alexander G; Osterfield, Miriam; Baker, Ruth E et al. (2014) Vertex models of epithelial morphogenesis. Biophys J 106:2291-304