During development, epithelial cells in many tissues acquire a polarity orthogonal to their apical-basal axis. This polarity, referred to as planar cell polarity (PCP), or tissue polarity, is essential for normal physiological function. Early studies of PCP focused on insect epithelia, and indeed, most of our mechanistic understanding of PCP derives from the ongoing use of the fruit fly, Drosophila, as a model system. However, a range of medically important developmental defects and physiological processes are under control of PCP mechanisms that appear to conserve much or all of the mechanism uncovered in flies, driving considerable interest in studying PCP both in Drosophila and in vertebrate model systems. Defects in PCP result in a range of developmental anomalies and diseases. Perhaps best characterized among these, PCP is required for the correct orientation of sensory hair cells in the organ of Corti of the inner ear, and defects result in deafness. Other PCP related developmental defects in humans and in model organisms include open neural tube defects, polycystic kidneys, and conotruncal heart defects. PCP is also believed to underlie the pathogenesis of idiopathic pulmonary hypertension and the directed migration that occurs during invasion and metastasis of malignant cells. Despite considerable progress in recent years, the molecular mechanisms of the PCP signaling modules and the interactions between them are as yet insufficiently understood, thereby limiting the potentially substantial opportunities for therapeutic interventions for these disorders. The goal of this proposal is to apply sophisticated genetics, microscopy and biochemical/proteomic methods to the study of PCP in the fruit fly. By doing so, we expect to advance our understanding of this important mechanism, and facilitate the development of diagnostic and therapeutic tools for these PCP-based disorders.

Public Health Relevance

Defects in planar cell polarity (PCP) result in a range of developmental anomalies and diseases, including deafness, open neural tube defects, polycystic kidneys, and a specific class of heart defects. PCP is also believed to underlie the pathogenesis of idiopathic pulmonary hypertension and the directed migration that occurs during invasion and metastasis of malignant cells.
We aim to better understand the molecular mechanisms of PCP, and thereby facilitate the development of diagnostic and therapeutic approaches for these disorders

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM059823-10S1
Application #
8186829
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Haynes, Susan R
Project Start
2000-09-01
Project End
2014-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
10
Fiscal Year
2011
Total Cost
$31,206
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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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
Matis, Maja; Russler-Germain, David A; Hu, Qie et al. (2014) Microtubules provide directional information for core PCP function. Elife 3:e02893
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
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
Stubbs, J L; Vladar, E K; Axelrod, J D et al. (2012) Multicilin promotes centriole assembly and ciliogenesis during multiciliate cell differentiation. Nat Cell Biol 14:140-7
Vladar, Eszter K; Bayly, Roy D; Sangoram, Ashvin M et al. (2012) Microtubules enable the planar cell polarity of airway cilia. Curr Biol 22:2203-12
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
Bayly, Roy; Axelrod, Jeffrey D (2011) Pointing in the right direction: new developments in the field of planar cell polarity. Nat Rev Genet 12:385-91

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