Nuclear Positioning is Important for the Survival of Mechanically Active Sensory Cells in the Cochlea
Authors: Horn Henning , Burke Brian , Stewart Colin 
Published: July 2019

Hearing loss is a common sensory deficit that can affect all levels of society. The two age groups where hearing loss is most likely to be identified is in newborns and in the elderly. Newborn screens have been very effective in finding individuals affected by hearing loss. The general hearing loss incidence in newborns is 0.2%, with roughly 50% of all cases being hereditary. A recent study in Qatar found that the incidence of hearing loss in newborns was as high as 5.2% 1, 25 times higher than the general global incidence. Much of this increase can be attributed to hereditary forms of hearing loss, as the rate of consanguinity in Qatar is high 1,2. The elderly are the other population group where hearing loss is often identified. Globally, the hearing loss incidence for people over 50 is around 40%, with men showing a higher incidence than women 3,4. In Qatar, 66% of the Qatari population over the age of 50 suffers hearing loss, compared to ∼35% for the non-Qatari populations 5. The gender distribution of hearing loss within the Qatari population is also different from the global trend, with the incidence being 75% for women and 59% percent for men5. Therefore, the incidence of hearing loss is dramatically higher in the Qatari population than it is globally, and presents an important health issue that should be addressed. We have previously shown that the outer nuclear membrane protein Nesprin 4 is essential for hearing in humans and in mice. Nesprin 4 is expressed in the sensory outer hair cells (OHCs) of the cochlea and is important for the proper nuclear positioning and survival of these cells. In the absence of functional Nesprin 4, the nuclei are apically mispositioned and the OHCs die. OHCs act as cochlear amplifiers, augmenting sound signals by up to 100-fold6. This amplification is achieved, at least in part, through electromotility, a somatic cell motility that causes cell length changes in response to depolarization or hyperpolarization of the cell. Electromotility is mediated by SLC26A5/prestin, a membrane protein enriched in the lateral membranes of OHCs7. Prestin-mediated electromotility develops postnatally in mice, with full activity occurring at 12–14 days after birth. We observed that the majority of OHCs in mice lacking Nesprin 4 die around this time and predicted that the mislocalized nucleus was incompatible with electromotility. To test this hypothesis we generated double-null mice for Nesprin 4 and prestin and examined the fate of OHCs in these animals. We found that loss of prestin rescues the loss of OHCs in Nesprin 4-null animals, indicating that while a mispositioned nucleus is incompatible with electromotility, it does not affect cell viability independent of mechanical stress. Others have previously shown that animals heterozygous for the prestin allele exhibit a reduced electromotility. We predicted that a reduction in electromotility should yield a partial rescue of OHCs in Nesprin 4-null animals. When we examine the Nesprin 4-null/prestin heterozygous animals, we did indeed observe a partial rescue of OHCs. Together, these results indicate that proper nuclear positioning mediated by Nesprin 4 in OHCs is essential for these cells to survive the mechanical stress of electromotility.References1. Bener, A., EIHakeem, A. A. M. & Abdulhadi, K. Is there any association between consanguinity and hearing loss. Int J Pediatr Otorhinolaryngol 69, 327–333 (2005).2. Girotto, G. et al. Consanguinity and Hereditary Hearing Loss in Qatar. Hum Hered 77, 175–182 (2014).3. Roberts, A. Sensorineural Hearing Loss. Synopsis of Causation, Ministry of Defence 1–30 (2008).4. Action on Hearing Loss. at < http://www.actiononhearingloss.org.uk/your-hearing/about-deafness-and-hearing-loss/statistics.aspx>5. Bener, A., Salahaldin, A. H., Darwish, S. M., Al-Hamaq, A. & Gansan, L. Association between hearing loss and type 2 diabetes mellitus in elderly people in a newly developed society. Biomed Res 19, 187–195 (2008).6. Liberman, M. C. et al. Prestin is required for electromotility of the outer hair cell and for the cochlear amplifier. Nature 419, 300–304 (2002).7. Dallos, P. & Fakler, B. PRESTIN, A NEW TYPE OF MOTOR PROTEIN. Nat Rev Mol Cell Biol 3, 104–111 (2002).