The Planar Cell Polarity (PCP) system polarizes cells in diverse epithelial sheets along an axis orthogonal to their apical-basal axis, and is necessary for numerous physiological functions. Studies in the fruit fly, Drosophila, have led to the concept of a modular system controlling PCP, in which functional modules each comprise a genetically and biochemically related unit. However, studies in different tissues and compartments have led to different models for how these modules are interconnected. We have recently identified unifying features, yet we also find unexpected differences in signaling architecture. This variation is likely also to be reflected in the adaptations of PCP signaling to the range of vertebrate functions it controls. Starkly different schemas for the connectivity between the two most understood modules, the Ft/Ds/Fj global module, the core module, and their downstream effector modules have been proposed based on studies in different epithelia, suggesting either a series (green and black pathways) or parallel (red and black) architecture. These analyses did not account for potential contributions of other global modules. Here, I propose to define the connectivity between modules across different compartments and determine whether signals from global modules converge on the core module or produce bypass signals to effector modules. Furthermore, isoforms of Prickle (Pk) are essential regulators of the link between the Ft/Ds/Fj and core modules. We have identified a unique function for these isoforms in modulating the polarity of microtubules that translate directional information between these modules. Yet, our data reveal that the current isoform model for Pk is incomplete. I propose to re-define the Pk isoforms and to search for Pk interacting proteins using state-of-the-art molecular methods.

Public Health Relevance

The Planar Cell Polarity (PCP) system polarizes cells in diverse epithelial sheets along an axis orthogonal to their apical-basal axis, and is necessary for numerous physiological functions. Defects in PCP signaling result in a range of developmental (birth) defects and impairments of physiological functions such as wound healing, and may be involved in the metastatic behavior of cancers. We propose studies that will illuminate the variations in signaling used by this pathway in various tissues in the fruit fly, Drosophila, and propose that these will help to understand the diverse ways this mechanism is deployed in vertebrates.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM097081-08
Application #
9623963
Study Section
Intercellular Interactions Study Section (ICI)
Program Officer
Hoodbhoy, Tanya
Project Start
2011-04-01
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Sharp, Katherine A; Axelrod, Jeffrey D (2016) Prickle isoforms control the direction of tissue polarity by microtubule independent and dependent mechanisms. Biol Open 5:229-36
Matis, Maja; Russler-Germain, David A; Hu, Qie et al. (2014) Microtubules provide directional information for core PCP function. Elife 3:e02893
Olofsson, Jessica; Sharp, Katherine A; Matis, Maja et al. (2014) Prickle/spiny-legs isoforms control the polarity of the apical microtubule network in planar cell polarity. Development 141:2866-74
Olofsson, Jessica; Axelrod, Jeffrey D (2014) Methods for studying planar cell polarity. Methods 68:97-104
Ehaideb, Salleh N; Iyengar, Atulya; Ueda, Atsushi et al. (2014) prickle modulates microtubule polarity and axonal transport to ameliorate seizures in flies. Proc Natl Acad Sci U S A 111:11187-92
Matis, Maja; Axelrod, Jeffrey D (2013) Regulation of PCP by the Fat signaling pathway. Genes Dev 27:2207-20
Peng, Ying; Axelrod, Jeffrey D (2012) Asymmetric protein localization in planar cell polarity: mechanisms, puzzles, and challenges. Curr Top Dev Biol 101:33-53
Abate, Alessandro; Vincent, St├ęphane; Dobbe, Roel et al. (2012) A mathematical model to study the dynamics of epithelial cellular networks. IEEE/ACM Trans Comput Biol Bioinform 9:1607-20
Peng, Ying; Han, Chun; Axelrod, Jeffery D (2012) Planar polarized protrusions break the symmetry of EGFR signaling during Drosophila bract cell fate induction. Dev Cell 23:507-18
Matis, Maja; Axelrod, Jeffrey D; Galic, Milos (2012) A universal analysis tool for the detection of asymmetric signal distribution in microscopic images. Dev Dyn 241:1301-9

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