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Molecular Components of Hair Cell Transduction
Unlike other senses such as vision and olfaction, the molecular basis of transduction in sensory hair cells is relatively unexplored. The search for the components of the transduction apparatus of hair cells has been an ongoing effort for the past two decades. Why have these molecules been so elusive? It is estimated that each hair cell has approximately 100 channels. Due to the limiting amount of material, purification of the transduction components is considered by most to be nearly impossible. Efforts to clone the transducer channel using PCR techniques have also not been successful. This is probably due to a lack of a distinguishing feature that allows the channel to be identified using molecular biological tools. Although human geneticists have made remarkable progress in identifying genes responsible for deafness, none of these candidates appear to represent the transduction apparatus. One molecule, a novel cadherin, has recently been thrown into the spotlight. Mutations in cadherin 23 cause deafness in humans, mice, and zebrafish. Based on studies in the Nicolson lab and collaborative efforts among labs at the Scripps Institute and the Gillespie lab, cadherin 23 appears to fulfill all of the requirements expected for the hair-cell tip link: (i) it localizes to stereociliary tips in zebrafish, bullfrogs, and mice; (ii) it is sensitive to calcium chelators, as are tip links; (iii) the extracellular domain of cadherin 23 is predicted to be long enough to span the distance between stereocilia; (iv) mutant cadherin 23 zebrafish lack tip links. If cadherin 23 is the tip link, then what is the interacting transduction channel? Despite the number of deafness genes identified in vertebrates, the most promising candidate for the transduction channel comes from studies in Drosophila. Richard Walker and colleagues characterized mechanotransduction currents in no mechanoreceptor potential (nomp) fly mutants and found a defect in adaptation in the mutant, nompC. nompC encodes a novel TRP channel. This finding initially caused some excitement; however, orthologues in the mouse and human database were not found. Nevertheless, in terms of physiology, both mechanosensory systems are strikingly analogous. Could it be that both systems evolved independently? Experiments from the Nicolson lab suggest that this is not the case. They identified a zebrafish nompC ortholog and demonstrated that it is required for mechanotransduction in sensory hair cells. Injection of antisense oligonucleotides caused a defect in balance and hearing, and extracellular receptor potentials in hair cells were absent in injected animals. Thus, by using either a forward or reverse genetic approach with the zebrafish, the lab was able to identify candidates for the tip link and transduction channel in vertebrate hair cells.
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