The evolutionarily conserved planar cell polarity (PCP) pathway (or noncanonical Wnt pathway) drives several important cellular processes, including epithelial cell polarization, cell migration and mitotic spindle orientation. In vertebrates, PCP genes have a vital role in polarized convergent extension movements during gastrulation and neurulation. Here we show that mice with mutations in genes involved in Bardet-Biedl syndrome (BBS), a disorder associated with ciliary dysfunction, share phenotypes with PCP mutants including open eyelids, neural tube defects and disrupted cochlear stereociliary bundles. Furthermore, we identify genetic interactions between BBS genes and a PCP gene in both mouse (Ltap, also called Vangl2) and zebrafish (vangl2). In zebrafish, the augmented phenotype results from enhanced defective convergent extension movements. We also show that Vangl2 localizes to the basal body and axoneme of ciliated cells, a pattern reminiscent of that of the BBS proteins. These data suggest that cilia are intrinsically involved in PCP processes.

In the 50 years since their discovery, the aminoglycoside antibiotics have seen unprecedented use. Discovered in the 1940s, they were the long-sought remedy for tuberculosis and other serious bacterial infections. The side effects of renal and auditory toxicity, however, led to a decline of their use in most countries in the 1970s and 1980s. Nevertheless, today the aminoglycosides are still the most commonly used antibiotics worldwide thanks to the combination of their high efficacy with low cost. This review first summarizes the history, chemistry, antibacterial actions and acute side effects of the drugs. It then details the pathophysiology of aminoglycoside ototoxicity including experimental and clinical observations, risk factors and incidence. Pharmacokinetics, cellular actions and our current understanding of the underlying molecular mechanisms of ototoxicity are discussed at length. The review concludes with recent advances towards therapeutic intervention to prevent aminoglycoside ototoxicity.

Supporting cells in the vestibular sensory epithelia from the ears of mature guinea pigs and adult humans proliferate in vitro after treatments with aminoglycoside antibiotics that cause sensory hair cells to die. After 4 weeks in culture, the epithelia contained new cells with some characteristics of immature hair cells. These findings are in contrast to expectations based on previous studies, which had suggested that hair cell loss is irreversible in mammals. The loss of hair cells is responsible for hearing and balance deficits that affect millions of people.

Planar cell polarity (PCP) is a process in which cells

It has long been thought that hair cell loss from the inner ears of mammals is irreversible. This report presents scanning electron micrographs and thin sections of the utricles from the inner ears of guinea pigs that show that, after hair cell loss caused by treatment with the aminoglycoside gentamicin, hair cells reappeared. Four weeks after the end of treatment, a large number of cells with immature hair bundles in multiple stages of development could be identified in the utricle. Thin sections showed that lost type 1 hair cells were replaced by cells with a morphology similar to that of type 2 hair cells. These results indicate an unexpected capacity for hair cell regeneration in vivo in the mature mammalian inner ear.