PCP in vertebrate systems

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. For example, each cell on the adult fly cuticle produces a trichome that emerges from the distal side of the cell, and each sensory hair cell in the mammalian organ of Corti organizes its stereocilia in crescents on the abneural side of the cell. In vertebrates, disruption of these processes gives rise to a variety of developmental defects and disease states. Studies in the fruitfly, 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, is used in tissue specific ways to produce a variety of morphologic manifestations. Among these are the orientation of multiciliated cells in the upper airway so that their cilia beat coordinately in the correct direction, and the orientation of renal tubule cells that enables them to undergo directional rearrangement and oriented cell divisions, both of which serve to regulate and maintain the proper tubule diameter.

Genetic and molecular analyses in Drosophila have identified components of the PCP signaling mechanism, and have suggested that they may be divided into three modules: a global directional module, a core module and tissue specific effector modules that respond to the upstream signals to produce various manifestations of morphological asymmetry.

Evidence is emerging to suggest that a conserved core module 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 as the global directional cue 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. In vertebrates, there exists a poorly understood relationship between primary cilia are 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 are addressing 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.