Identification of Vangl2 and Scrb1 as planar polarity genes in mammals

Abstract

In mammals, an example of planar cell polarity (PCP) is the uniform orientation of the hair cell stereociliary bundles within the cochlea. The PCP pathway of Drosophila refers to a conserved signalling pathway that regulates the coordinated orientation of cells or structures within the plane of an epithelium. Here we show that a mutation in Vangl2, a mammalian homologue of the Drosophila PCP gene Strabismus/Van Gogh, results in significant disruptions in the polarization of stereociliary bundles in mouse cochlea as a result of defects in the direction of movement and/or anchoring of the kinocilium within each hair cell. Similar, but less severe, defects are observed in animals containing a mutation in the LAP protein family gene Scrb1 (homologous with Drosophila scribble). Polarization defects in animals heterozygous for Vangl2 and Scrb1 are comparable with Vangl2 homozygotes, demonstrating genetic interactions between these genes in the regulation of PCP in mammals. These results demonstrate a role for the PCP pathway in planar polarization in mammals, and identify Scrb1 as a PCP gene.

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

“…At the 50% level, OHC3 has 61% misalignment, while OHC2 and 1 have 36% and 12%, respectively, and the IHC layer has only 11%. This pattern is more similar to that seen in PCP mutants such as circletail (Scrib1), and PTK7 (Montcouquiol et al, 2003;Lu et al, 2004), where the OHC3 is predominantly affected and the IHC is relatively unaffected. Cecr2 and Ptk7 mutants show other similarities.…”

“…Vangl2 mRNA shows similar expression in both locations at 14.5 dpc and 16.5 dpc (Montcouquiol et al, 2003). Celsr1, Dvl1, and Dvl2 are found in the statoacoustic ganglion (Wang et al, 2005).…”

“…Stereocilia bundle analysis was modeled after (Montcouquiol et al, 2003) with few deviations. The sensory epithelium was imaged using confocal microscopy at the basal (5%), middle (50%), and apical (75%) positions.…”

“…A ''core'' set of PCP genes was established in Drosophila (Fanto and McNeill, 2004). Homologues in vertebrates include Vangl1/ 2, Frizzled3 and 6, Disheveled1-3, Celsr1, Prickle, Scribbled, PTK7, and Ankrd6 (Schwarz-Romond et al, 2002;Carreira-Barbosa et al, 2003;Curtin et al, 2003;Montcouquiol et al, 2003;Lu et al, 2004;Wang et al, 2006a,b;Torban et al, 2007). Examples of PCP can be observed throughout vertebrate embryogenesis, most notably in the convergent extension (CE) movements required to elongate and shape the neural epithelium during early neurulation, as well as the highly organized epithelium within the cochlear sensory structures (Park and Moon, 2002;Wang et al, 2005).…”

“…PCP has also been implicated in the cell movements that form the eyelid (Murdoch et al, 2001;Wang and Nathans, 2007). Defects in PCP genes constitute approximately 5% of all known murine NTD mutations and are usually associated with craniorachischisis (a lack of neural tube closure throughout its length), open eyelids, and rotational defects of the cochlear sensory cells (Kibar et al, 2001;Murdoch et al, 2001;Hamblet et al, 2002;Curtin et al, 2003;Montcouquiol et al, 2003;Lu et al, 2004;Wang et al, 2006b;Harris and Juriloff, 2007;Torban et al, 2008).…”