Prickle Mediates Feedback Amplification to Generate Asymmetric Planar Cell Polarity Signaling

Abstract

Planar cell polarity signaling in Drosophila requires the receptor Frizzled and the cytoplasmic proteins Dishevelled and Prickle. From initial, symmetric subcellular distributions in pupal wing cells, Frizzled and Dishevelled become highly enriched at the distal portion of the cell cortex. We describe a Prickle-dependent intercellular feedback loop that generates asymmetric Frizzled and Dishevelled localization. In the absence of Prickle, Frizzled and Dishevelled remain symmetrically distributed. Prickle localizes to the proximal side of pupal wing cells and binds the Dishevelled DEP domain, inhibiting Dishevelled membrane localization and antagonizing Frizzled accumulation. This activity is linked to Frizzled activity on the adjacent cell surface. Prickle therefore functions in a feedback loop that amplifies differences between Frizzled levels on adjacent cell surfaces.

Essential role of non-canonical Wnt signalling in neural crest migration

“…An important feature of the PCP molecular mechanism is its effects on asymmetrically localized molecules. This has been particularly well studied in the wing, where Flamingo, Diego, Frizzled, Dishevelled, Strabismus and Prickle become localized along the proximodistal axis of the cells (Axelrod, 2001;Bastock et al, 2003;Feiguin et al, 2001;Shimada et al, 2001;Tree et al, 2002;Usui et al, 1999). A large body of evidence suggests that Fz has a key role in sensing positional information; although what is upstream of Fz remains unknown.…”

Controlled levels of canonical Wnt signaling are required for neural crest migration

“…Activation of proteins belonging to the Rho family of small GTPases occurs mainly through the planar cell polarity (PCP) pathway, which was extensively studied in the fruit fly Drosophila melanogaster where it controls the proximal-distal orientation of hair and bristles on the body (Klein and Mlodzik, 2005;Tree et al, 2002;Adler 2002).…”

“…The 'PCP' core components include several transmembrane proteins, such as Frizzled (Fz) (Adler et al, 1997;Vinson and Adler, 1987), Strabismus (Stbm)/Van Gogh (Vang) (Taylor et al, 1998;Wolff and Rubin, 1998), Flamingo (Fmi) (Chae et al, 1999;Usui et al, 1999) and intracellular proteins like Disheveled (Dsh) (Theisen et al, 1994), Prickle (Pk) and Diego (Dgo) (Feiguin et al, 2001). In the Drosophila wing cells, all of those proteins are initially uniformly distributed in the whole cell membrane, however, upon mutual interactions they become asymmetrically segregated; Fz, Dsh and Dgo accumulate at the distal and Stbm/Vang and Pk at the proximal edge of the cell membrane (Axelrod, 2001;Strutt, 2001;Feiguin et al, 2001;Tree et al, 2002;Bastock et al, 2003). The atypical cadherin, Fmi resides on both distal and proximal edges, where it binds neighboring cells through heomophilic interactions (Usui et al, 1999;Shimada et al, 2001).…”

Morphogen gradients, positional information, and Xenopus: Interplay of theory and experiment

“…As for polarity, the way in which morphogen gradients provide both scalar and vectorial information to cells is almost definitive for true morphogens (Wolpert, 1969;Lawrence, 2001a). Recent progress has been made in understanding the detailed molecular mechanisms of planar polarity (e.g., Lawrence et al, 2002;Yang et al, 2002;Tree et al, 2002). The picture that emerges is that graded extracellular signals provide a bias for movement of specific molecules to one end of a cell or the other and that these intracellular distributions are reinforced by very local positive and negative feedback loops.…”