Wnt5a functions in planar cell polarity regulation in mice

Abstract

Planar cell polarity (PCP) refers to the polarization of cells within the plane of a cell sheet. A distinctive epithelial PCP in vertebrates is the uniform orientation of stereociliary bundles of the sensory hair cells in the mammalian cochlea. In addition to establishing epithelial PCP, planar polarization is also required for convergent extension (CE); a polarized cellular movement that occurs during neural tube closure and cochlear extension. Studies in Drosophila and vertebrates have revealed a conserved PCP pathway, including Frizzled (Fz) receptors. Here we use the cochlea as a model system to explore the involvement of known ligands of Fz, Wnt morphogens, in PCP regulation. We show that Wnt5a forms a reciprocal expression pattern with a Wnt antagonist, the secreted frizzled-related protein 3 (Sfrp3 or Frzb), along the axis of planar polarization in the cochlear epithelium. We further demonstrate that Wnt5a antagonizes Frzb in regulating cochlear extension and stereociliary bundle orientation in vitro, and that Wnt5a(-/-) animals have a shortened and widened cochlea. Finally, we show that Wnt5a is required for proper subcellular distribution of a PCP protein, Ltap/Vangl2, and that Wnt5a interacts genetically with Ltap/Vangl2 for uniform orientation of stereocilia, cochlear extension, and neural tube closure. Together, these findings demonstrate that Wnt5a functions in PCP regulation in mice.

Role of chromatin remodeling gene Cecr2 in neurulation and inner ear development

“…Unlike Cecr2, all the core PCP genes tested have also been found expressed in the sensory hair cells themselves (Wang et al, 2005;Jones and Chen, 2007;Seifert and Mlodzik, 2007). However, Wnt5a expression also appears in the cochlear floor and not the hair cells (Qian et al, 2007). The latter suggests that Cecr2 may play a role in cells controlling signals that act externally on the hair cells to provide orientation.…”

“…Although associated with canonical Wnt signaling, Lrp6 is necessary for Xenopus convergent extension (Tahinci , 2007), yet the exencephalic mice are of normal size, similar to Cecr2. Finally, mutation of Wnt5a results in inner ear defects and neural tube defects: of 34 Wnt5a null animals, 1 had craniorachischisis and 3 had exencephaly (Qian et al, 2007). Therefore, the presence of exencephaly rather than craniorachischisis is within the spectrum of PCP phenotype, although it may be indicative of a secondary or uncharacterized aspect in the pathway.…”

The Dishevelled-associating protein Daple controls the non-canonical Wnt/Rac pathway and cell motility

“…To this end, we utilised Wnt5a, a Wnt ligand protein that is known to signal via the non-canonical Wnt signalling pathway and stimulate the activation of Rac in cultured cells 17,25,40 . Time-dependent Rac activation induced by Wnt5a was attenuated by the knockdown of Daple (Fig.…”

Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling

“…Ror2 has been shown to act as a receptor or co-receptor for Wnt5a (Oishi et al, 2003;Mikels and Nusse, 2006;Nishita et al, 2006). In fact, both Ror2-and Wnt5a-mutant mice showed similar skeletal, cardiovascular, genital and inner ear abnormalities that are caused at least partly by disrupted planar cell polarity and convergent extension movements during development (Qian et al, 2007;Yamamoto et al, 2008). It has been shown that Ror2 mediates Wnt5a signaling by activating the Wnt/JNK pathway and inhibiting the b-catenin-TCF pathway (Oishi et al, 2003;Mikels and Nusse, 2006).…”