A major challenge in developmental biology is to understand how large-scale changes in tissue structure are generated on a cellular and molecular level. Two decades of research in molecular genetics have provided insight into the mechanisms that control cell fate and patterning, but the morphogenetic events that translate cell fate determination into the shapes of cells and tissues are not well understood. A conserved feature of tissue architecture in vertebrates and invertebrates is a body axis that is elongated from head to tail. Polarized cell rearrangements play a major role in shaping the body axis of several organisms. Cell rearrangements in epithelial tissues are constrained by a network of adherens junctions between cells whose continuity is maintained throughout elongation. Unique strategies for tissue elongation may therefore be utilized by epithelial cells that must dynamicall remodel cell adhesion without compromising epithelial integrity. Recent work has provided insight into the physical mechanisms that underlie the mechanics of force generation and cell adhesion during axis elongation. In particular, many proteins that are required for axis elongation, including components of the contractile machinery and cell-cell junctions, are asymmetrically localized in the plane of the tissue. This asymmetric localization appears to be crucial for planar polarized force generation and junctional remodeling during axis elongation. However, the upstream signals that generate spatially regulated actomyosin contractility and adhesion to align cell rearrangements with the global tissue axes are not well understood. We have shown that Rho-kinase and Abl tyrosine kinase are asymmetrically localized and control the distribution of contractile forces and cell adhesion dynamics during axis elongation. We hypothesize that these kinases respond to upstream spatial cues to generate spatially regulated contractility and adhesion, polarized cell rearrangement, and tissue elongation. We will use molecular genetic, cell biological, and quantitative imaging approaches to investigate the upstream spatial mechanisms that regulate the localization and activity of these two conserved protein kinases that are essential for axis elongation. In addition, we will use computational methods and fluorescent protein imaging to study the dynamic mechanisms by which planar polarity is established and remodeled throughout elongation. Junctional remodeling is important for epithelial morphogenesis during development, and defects in epithelial maintenance and repair in the adult are associated with diseases such as cystic kidney disease and tumor cell metastasis. A better understanding of the mechanisms that regulate epithelial elongation can elucidate general principles of epithelial organ formation and provide insight into how the misregulation of these processes leads to 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 defects in essential developmental processes such as neural tube closure.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM079340-06A1
Application #
8514293
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
2007-09-01
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$331,942
Indirect Cost
$144,192
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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
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
Tamada, Masako; Farrell, Dene L; Zallen, Jennifer A (2012) Abl regulates planar polarized junctional dynamics through ?-catenin tyrosine phosphorylation. Dev Cell 22:309-19
Kasza, Karen E; Zallen, Jennifer A (2011) Dynamics and regulation of contractile actin-myosin networks in morphogenesis. Curr Opin Cell Biol 23:30-8
Fernandez-Gonzalez, Rodrigo; Zallen, Jennifer A (2011) Oscillatory behaviors and hierarchical assembly of contractile structures in intercalating cells. Phys Biol 8:045005
Simões, Sérgio de Matos; Blankenship, J Todd; Weitz, Ori et al. (2010) Rho-kinase directs Bazooka/Par-3 planar polarity during Drosophila axis elongation. Dev Cell 19:377-88
Zallen, Jennifer A; Yap, Alpha S (2010) Morphogenesis in Kyoto: a confluence of cell and developmental biology. Mol Biol Cell 21:845-7
Martin, Adam C; Gelbart, Michael; Fernandez-Gonzalez, Rodrigo et al. (2010) Integration of contractile forces during tissue invagination. J Cell Biol 188:735-49
Wirtz-Peitz, Frederik; Zallen, Jennifer A (2009) Junctional trafficking and epithelial morphogenesis. Curr Opin Genet Dev 19:350-6
Fernandez-Gonzalez, Rodrigo; Simoes, Sergio de Matos; Roper, Jens-Christian et al. (2009) Myosin II dynamics are regulated by tension in intercalating cells. Dev Cell 17:736-43

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