During mammalian neural development, cells extend projections to target tissues from which they derive growth factors needed for survival. Initially, neurons of the inner ear require brain-derived neurotrophic factor (Bdnf) and neurotrophin 3 (Ntf3) from the otic placode, the sensory epithelium from which the cells are derived. Later, the cells express these growth factors themselves, which support the neurons that project to them.
Although this process is well known, the underlying molecular mechanisms have been unclear. Slitrk6, a transmembrane protein with structural similarities to the Slit family of axon guidance molecules and to the Ntrk neurotrophic factor receptors, is known to be expressed in the otic placode, and is therefore likely to play a role in inner ear development.
To investigate this, Kei-ichi Katayama of the RIKEN Brain Science Institute and his colleagues generated mice lacking the Slitrk6 gene. They found that the gross structure of the inner appeared normal1. However, they observed a significant reduction in the number of nerve fiber bundles projecting to the cochlea (Fig. 1). These defects were evident during late embryonic stages, and persisted throughout postnatal development. In the vestibular region, the defects were more severe, with nerve fibers bundles completely absent in this region in most mutant animals. In others, they were significantly reduced or had abnormal trajectories.
Next the researchers examined the spiral and vestibular ganglia, which contain neurons that project to the cochlea and vestibular region, respectively. Cell death was significantly higher in the mutants than in wild-type animals, so that the structures were up to 75% smaller than normal by the time of birth.
They also found that cultured sensory neurons from the spiral ganglion of mutant mice could grow projections towards sensory epithelial tissue from normal, but not mutant, mice. Further experiments revealed a mild but significant reduction in levels of Bdnf and Ntf-3 in the developing inner ear of the mutants. The phenotype of the mutant mice is therefore not due to axon guidance defects. Instead, these results suggest that Slitrk6 is part of a signaling pathway that increases expression of Bdnf and Ntf3 in the sensory epithelia.
“Behavioral tests show that the Slitrk6 knockout mice exhibit hearing loss,” says senior author Jun Aruga, “and we are now investigating whether they also have balance deficits. We believe our mutant mice are a good animal model of sensorineural deafness, which occurs because of improper cochlear development, following over-exposure to loud noises, and as a result of aging.”
The corresponding author for this highlight is based at the Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute
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