The cells in many epithelia are polarized along an axis orthogonal to their apical-basal axis. This polarization, referred to as Planar Cell Polarity (PCP), is necessary for numerous developmental processes and physiological functions. In vertebrates, disruption of these processes gives rise to a variety of developmental defects and disease states. Studies in the fruit fly, Drosophila, have produced an emerging understanding of the molecular mechanisms controlling PCP, and strong evidence indicates conservation of key elements of this mechanism in at least some vertebrate tissues, although novel, vertebrate specific elements have also been identified. In both flies and vertebrates, molecular polarization, based on a common mechanism, produces a variety of morphologic manifestations. Among these are the orientations of multiciliated cells in the upper airway so that their cilia beat in the correct direction and the orientation of renal tubule cells that enables them to undergo directional rearrangement and oriented cell divisions that regulate and maintain tubule diameter. Genetic and molecular analyses in Drosophila have identified components of the PCP signaling mechanism, and have led to an emerging understanding of the mechanism by which they interpret and communicate polarity information. The mechanism leads to the collective molecular polarization of cells, in which a set of conserved PCP proteins communicate at cell boundaries, recruiting one subset of these proteins to the distal side of cells, and another subset to the proximal side, thereby aligning the polarity of adjacent cells. These proteins also produce localized signals that orient the various effectors of morphological polarization. Evidence is emerging to suggest that a conserved group of proteins polarizes and aligns cells with each other in some vertebrate epithelia, although scant mechanistic data exist. There is relatively little knowledge of the signal(s) that serve to globally orient PCP in vertebrates, or if this mechanism is conserved from flies. Furthermore, vertebrate PCP depends on elements not used in flies. Wnt signals are essential in vertebrate PCP, though the best evidence indicates no role for Wnts in Drosophila PCP, and primary cilia are implicated in vertebrate PCP, yet primary cilia are absent in most fly tissues. Finally, little is known about how vertebrate tissues use the PCP signal to execute polarized morphological differentiation. We will address these questions using a powerful combination of in vivo genetic and in vitro culture models of PCP in two mouse epithelial tubes: the multiciliated epithelium of the trachea and the renal tubule. Together, these studies will increase our knowledge of the shared signaling mechanisms that regulate vertebrate PCP, thereby shedding light on the etiology of a range of PCP-dependent developmental anomalies and disease processes. They will also help us to understand in greater detail two specific PCP-dependent diseases, including a class of Primary Ciliary Dyskinesia syndromes and polycystic kidney disease.

Public Health Relevance

Defects in planar cell polarity (PCP) result in a range of developmental anomalies and diseases including polycystic kidney disease and primary ciliary dyskinesia, open neural tube disorders, deafness, and a 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. Studies in the fruit fly, Drosophila, have produced an emerging understanding of the molecular mechanisms controlling PCP, and strong evidence indicates conservation of key elements of this mechanism in at least some vertebrate tissues, although novel, vertebrate specific elements have also been identified. This project will leverage our understanding from the fruit fly to produce a much deeper mechanistic understanding of vertebrate PCP. This understanding will be important in developing therapies to reduce the considerable morbidity and mortality associated with polycystic kidney disease, primary ciliary dyskinesia as well as the whole range of PCP- associated disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098582-02
Application #
8302269
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
2011-07-18
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$394,830
Indirect Cost
$154,828
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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
Tao, Hirotaka; Inoue, Ken-ichi; Kiyonari, Hiroshi et al. (2012) Nuclear localization of Prickle2 is required to establish cell polarity during early mouse embryogenesis. Dev Biol 364:138-48