The diverse shapes of multicellular organisms are established during development by spatially and temporally regulated changes in cell shape and behavior. A major morphogenetic movement in multicellular organisms is the reorganization of cells to form the elongated head-to-tail body axis. This conserved process requires a striking directionality in which populations of cells align their movements with the body axes, referred to as cell intercalation. Cell intercalation in epithelial tissues occurs in the presence of a networkof adherens junctions that transmits mechanical forces between cells and maintains its integrity as cells make and break contacts throughout cell rearrangement. Genetic studies have provided insight into the biochemical signals that regulate cell fate and behavior, but much less is known about how cells sense and respond to mechanical signals to translate mechanical forces into directional cell movement. In the Drosophila embryo, the polarized cell rearrangements that drive body axis elongation are guided by the spatial and temporal regulation of contractile actomyosin networks. However, the molecular mechanisms that mediate force-dependent myosin regulation are not well understood. The long-term goal of these studies is to obtain insight into how cells translate mechanical forces into biochemical signals to generate three-dimensional tissue structure during development. The overall objective of this proposal is to characterize the molecular basis of the mechanotransduction pathway that regulates myosin localization in intercalating cells and investigate how this mechanism influences the three-dimensional cell behaviors that shape the Drosophila body axis. We will use high-throughput computational methods we have developed to analyze in vivo myosin localization in the Drosophila embryo and compare myosin dynamics with the distributions of other proteins involved in contractility and cell adhesion. We will use biophysical, live imaging and quantitative computational approaches to characterize the molecular mechanisms that translate mechanical forces into a change in myosin localization. In addition, we will analyze cell shape and behavior in three dimensions during axis elongation and characterize the defects in embryos lacking specific proteins. Mechanical forces have been shown to influence many aspects of tissue development, including blood vessel remodeling, lung branching morphogenesis, and development of the heart, kidney, mammary gland, and bone. These studies will identify the mechanisms by which mechanical forces regulate myosin localization and activity and provide information relevant to the treatment and prevention of human diseases that involve defects in mechanical cell regulation, including atherosclerosis, osteoporosis, and tumor progression to metastasis.

Public Health Relevance

Mechanical forces have been shown to regulate many aspects of tissue development, including blood vessel remodeling, lung branching morphogenesis, and development of the heart, kidney, mammary gland, and bone. However, the mechanisms by which cells sense and respond to mechanical signals are not well understood. Here we will investigate the mechanical mechanisms that regulate the cell behaviors that shape the Drosophila body axis. These studies will provide insight into how cells translate mechanical forces into biochemical signals to generate three-dimensional tissue structure during development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM102803-01
Application #
8335744
Study Section
Special Emphasis Panel (ZRG1-CB-P (55))
Program Officer
Hoodbhoy, Tanya
Project Start
2012-09-30
Project End
2016-06-30
Budget Start
2012-09-30
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$337,469
Indirect Cost
$144,593
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Simões, Sérgio de Matos; Mainieri, Avantika; Zallen, Jennifer A (2014) Rho GTPase and Shroom direct planar polarized actomyosin contractility during convergent extension. J Cell Biol 204:575-89
Kasza, Karen E; Farrell, Dene L; Zallen, Jennifer A (2014) Spatiotemporal control of epithelial remodeling by regulated myosin phosphorylation. Proc Natl Acad Sci U S A 111:11732-7
Paré, Adam C; Vichas, Athea; Fincher, Christopher T et al. (2014) A positional Toll receptor code directs convergent extension in Drosophila. Nature 515:523-7