Involvement of programmed cell death in morphogenesis of the vertebrate inner ear.

An outstanding challenge in developmental biology is to reveal the mechanisms underlying the morphogenesis of complex organs. A striking example is the developing inner ear of the vertebrate, which acquires a precise three-dimensional arrangement of its constituent epithelial cells to form three semicircular canals, a central vestibule and a coiled cochlea (in mammals). In generating a semicircular canal, epithelial cells seem to 'disappear' from the center of each canal. This phenomenon has been variously explained as (i) transdifferentiation of epithelium into mesenchyme, (ii) absorption of cells into the expanding canal or (iii) programmed cell death. In this study, an in situ DNA-end labeling technique (the TUNEL protocol) was used to map regions of cell death during inner ear morphogenesis in the chicken embryo from embryonic days 3.5-10. Regions of cell death previously identified in vertebrate ears have been confirmed, including the ventromedial otic vesicle, the base of the endolymphatic duct and the fusion plates of the semicircular canals. New regions of cell death are also described in and around the sensory organs. Reducing normal death using retrovirus-mediated overexpression of human bcl-2 causes abnormalities in ear morphogenesis: hollowing of the center of each canal is either delayed or fails entirely. These data provide new evidence to explain the role of cell death in morphogenesis of the semicircular canals.