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.

The mammalian cochlea contains an invariant mosaic of sensory hair cells and non-sensory supporting cells reminiscent of invertebrate structures such as the compound eye in Drosophila melanogaster. The sensory epithelium in the mammalian cochlea (the organ of Corti) contains four rows of mechanosensory hair cells: a single row of inner hair cells and three rows of outer hair cells. Each hair cell is separated from the next by an interceding supporting cell, forming an invariant and alternating mosaic that extends the length of the cochlear duct. Previous results suggest that determination of cell fates in the cochlear mosaic occurs via inhibitory interactions between adjacent progenitor cells (lateral inhibition). Cells populating the cochlear epithelium appear to constitute a developmental equivalence group in which developing hair cells suppress differentiation in their immediate neighbours through lateral inhibition. These interactions may be mediated through the Notch signalling pathway, a molecular mechanism that is involved in the determination of a variety of cell fates. Here we show that genes encoding the receptor protein Notch1 and its ligand, Jagged 2, are expressed in alternating cell types in the developing sensory epithelium. In addition, genetic deletion of Jag2 results in a significant increase in sensory hair cells, presumably as a result of a decrease in Notch activation. These results provide direct evidence for Notch-mediated lateral inhibition in a mammalian system and support a role for Notch in the development of the cochlear mosaic.

ABSTRACTnumber of cells as compared with wildtype, while transcripts for HES5 are dramatically reduced throughout the epithelium. These results are consistent with the The sensory epithelium within the mammalian hypothesis that activation of Notch via Jagged2 acts to cochlea (the organ of Corti) is a strictly ordered celluinhibit expression of Math1 in cochlear progenitor lar array consisting of sensory hair cells and nonsencells, possibly through the activity of HES5. sory supporting cells. Previous research has

Fish (Astronotus ocellatus, the oscar) were subject to pure tones in order to determine the effects of sound at levels typical of man-made sources on the sensory epithelia of the ear and the lateral line. Sounds varied in frequency (60 or 300 Hz), duty cycle (20% or continuous), and intensity (100, 140, or 180 dB re: 1 muPa). Fish were allowed to survive for 1 or 4 days posttreatment. Tissue was then evaluated using scanning electron microscopy to assess the presence or absence of ciliary bundles on the sensory hair cells on each of the otic endorgans and the lateral line. The only damage that was observed was in four of five fish stimulated with 300-Hz continuous tones at 180 dB re: 1 muPa and allowed to survive for 4 days. Damage was limited to small regions of the striola of the utricle and lagena. There was no damage in any other endorgan, and the size and location of the damage varied between specimens. No damage was observed in fish that had been allowed to survive for 1 day poststimulation, suggesting that damage may develop slowly after exposure.

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