How does a sensory hair cell convert mechanical energy such as sound into electrical signals? How does it transmit information to the brain?
A few years ago, Teresa Nicolson, whose work is focused on these questions, identified a molecule in hair cells that plays a key role in converting sound into electrical signals. The molecule, Cadherin 23, is part of a very long extracellular filament that creates links between the hair-like structures of a sensory hair cell. When sound sets the hair-like processes into motion, the tension created by Cadherin 23 is thought to physically open mechanosensitive channels.
To make this discovery, Nicolson used a relatively new model organism for the study of hearing and balance—the zebrafish. Large-scale mutagenesis screens enabled her to identify more than two dozen genes required for hearing and balance in the fishes' larval stage. To date, her lab has cloned 11 zebrafish genes that are selectively expressed in hair cells and are critical for either mechanotransduction or neurotransmitter release. She gave the genes names that ring of space exploration (sputnik, mercury, skylab) because the mutant fish behave like space travelers in zero gravity, unable to orient themselves or navigate normally. Mutations in many of the same genes are responsible for deafness in humans and mice.
Nicolson has also characterized mutations in protocadherin 15, another novel cadherin. As with cadherin 23, weak alleles of protocadherin 15 leave hair-like structures at the apical surface more or less intact, although mechanotransduction is greatly reduced or absent. This work provided some of the first evidence that Protocadherin 15 plays a functional role rather than a structural role in hair cells.
At the opposite end of the hair cell, the synapses communicate with nerves that project to the brain. The Nicolson lab has identified various molecules important for function of the hair-cell synapse, including Vesicular Glutamate Transporter 3, which packages neurotransmitter into synaptic vesicles, and synaptojanin, which is important for synaptic vesicle recycling. Defects in synaptic vesicle recycling lead to less than perfect timing of release of vesicles that are "in phase" with or coupled to mechanical stimuli. Thus, transmission of information about sounds or head movements to the brain is not accurate in synaptojanin mutants, affecting their ability to maintain balance.
Currently, the Nicolson lab is developing innovative ways to image the subcellular location of fluorescently tagged proteins and neuronal responses in hair cells in transgenic zebrafish. Live imaging allows her lab to watch calcium flow into the hair bundles at the apical end (mechanotransduction) and to observe the biogenesis or functional aspects of a synapse at the base of the cell in an intact animal. These experiments are possible because zebrafish are perfectly transparent at the larval stage and have sensory hair cells at the surface of the skin.
