Robert Fettiplace, Ph.D.
Steenbock Professor of Neural and Behavioral Sciences
Department of Neuroscience
University of Wisconsin-Madison
Hair cell death and deafness in TMC1 mutation
Death (or apoptosis) of cochlear hair cells occurs under various conditions, some genetic and others environmental. Since hair cells do not regenerate, these insults all lead to permanent deafness. We have studied the mechanisms of hair cell death in mice with mutations in TMC1, which is the putative mechanotransducer channel. Such hair cell mutants show functional mechano-transduction at P6 but die culminating in deafness by P20. What is the mechanism? We have found that even at an early developmental stage, cochlear hair cells exhibit signs of apoptosis (cell death), revealed by dysfunctional mitochondria and the activity of a lipid scramblase that removes lipid asymmetry in the plasma membrane. Scramblase activity is triggered by blocking the PMCA2 calcium pump in the hair bundle, causing elevation of stereociliary calcium. The PMCA2 density is reduced in all the mutants, which is a possible mechanism of hair cell apoptosis and deafness.