A fundamental property of cells is their ability to act collectively to generate functional multicellular structures during tissue development, regeneration, and repair. An understanding of the mechanisms that organize cells into tissues is essential for treating developmental disorders and realizing the potential of tissue engineering and regenerative medicine. Cell- surface receptors expressed in precise patterns across tissues create spatial maps that control local interactions between cells and organize collective cell movements to establish tissue structure. How dynamic cell behaviors are organized in response to complex patterns of extracellular spatial information is not well understood. During convergent extension, the movements of hundreds of cells are systematically aligned with the tissue axes to elongate the body axis. This proposal aims to understand the mechanisms that regulate dynamic changes in cell polarity and interactions during this process, and to elucidate how cells respond to complex patterns of spatial information to achieve this conserved tissue structure. We discovered that three cell-surface proteins in the Toll receptor family create a spatial map that guides cell movements during convergent extension in Drosophila and directs the localization and activity of cellular proteins that generate contractile and adhesive forces within cells. Vertebrate Toll-like receptors respond to an extraordinary range of signals presented by fungi, bacteria, viruses, and parasites to elicit transcriptional changes that activate the innate immune response, but the mechanisms required for Toll receptor activation and signaling during convergent extension are not well understood. We will use genetic, cell biological, biochemical, and quantitative imaging approaches to determine how Toll receptors promote selective recognition between cells during development and identify the signaling mechanisms by which these receptors regulate cell polarity and behavior. Powerful genetic, cell biological, and quantitative imaging methods in Drosophila will be used to dissect the distinct spatial inputs of different members of this family of cell-surface receptors and investigate their functional contributions to cell behavior and tissue morphogenesis. These studies will elucidate mechanisms of Toll receptor activation and signaling and reveal general principles of tissue organization. A better understanding of how extracellular spatial cues are translated into changes in cell polarity and dynamics to establish tissue structure can provide insight into how the deregulation of these processes contributes to developmental disorders and human disease.

Public Health Relevance

A major challenge in developmental biology is to understand how the large-scale changes in tissue structure are generated on a cellular and molecular level. Interactions between cells are dynamically regulated as cells move and change shape during development. Here we propose to study how cell interactions shape the body axis of the developing embryo, which can provide insight into how the misregulation of adhesion can lead to developmental defects and tumor cell metastasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM079340-12
Application #
9983685
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hoodbhoy, Tanya
Project Start
2007-09-01
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
12
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Farrell, Dene L; Weitz, Ori; Magnasco, Marcelo O et al. (2017) SEGGA: a toolset for rapid automated analysis of epithelial cell polarity and dynamics. Development 144:1725-1734
Vichas, Athea; Laurie, Matthew T; Zallen, Jennifer A (2015) The Ski2-family helicase Obelus regulates Crumbs alternative splicing and cell polarity. J Cell Biol 211:1011-24
Tamada, Masako; Zallen, Jennifer A (2015) Square Cell Packing in the Drosophila Embryo through Spatiotemporally Regulated EGF Receptor Signaling. Dev Cell 35:151-61
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
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
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
Fernandez-Gonzalez, Rodrigo; Zallen, Jennifer A (2012) Feeling the squeeze: live-cell extrusion limits cell density in epithelia. Cell 149:965-7
Nance, Jeremy; Zallen, Jennifer A (2011) Elaborating polarity: PAR proteins and the cytoskeleton. Development 138:799-809
Vichas, Athea; Zallen, Jennifer A (2011) Translating cell polarity into tissue elongation. Semin Cell Dev Biol 22:858-64
Fernandez-Gonzalez, Rodrigo; Zallen, Jennifer A (2011) Oscillatory behaviors and hierarchical assembly of contractile structures in intercalating cells. Phys Biol 8:045005

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