title: Molecular remodeling of tip links underlies mechanosensory regeneration in auditory hair cells.
abstract: Sound detection by inner ear hair cells requires tip links that interconnect mechanosensory stereocilia and convey force to yet unidentified transduction channels. Current models postulate a static composition of the tip link, with protocadherin 15 (PCDH15) at the lower and cadherin 23 (CDH23) at the upper end of the link. In terminally differentiated mammalian auditory hair cells, tip links are subjected to sound-induced forces throughout an organism's life. Although hair cells can regenerate disrupted tip links and restore hearing, the molecular details of this process are unknown. We developed a novel implementation of backscatter electron scanning microscopy to visualize simultaneously immuno-gold particles and stereocilia links, both of only a few nanometers in diameter. We show that functional, mechanotransduction-mediating tip links have at least two molecular compositions, containing either PCDH15/CDH23 or PCDH15/PCDH15. During regeneration, shorter tip links containing nearly equal amounts of PCDH15 at both ends appear first. Whole-cell patch-clamp recordings demonstrate that these transient PCDH15/PCDH15 links mediate mechanotransduction currents of normal amplitude but abnormal Ca(2+)-dependent decay (adaptation). The mature PCDH15/CDH23 tip link composition is re-established later, concomitant with complete recovery of adaptation. Thus, our findings provide a molecular mechanism for regeneration and maintenance of mechanosensory function in postmitotic auditory hair cells and could help identify elusive components of the mechanotransduction machinery.
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Artur A
authors.initials: AA
authors.lastname: Indzhykulian
authors.forename: Ruben
authors.initials: R
authors.lastname: Stepanyan
authors.forename: Anastasiia
authors.initials: A
authors.lastname: Nelina
authors.forename: Kateri J
authors.initials: KJ
authors.lastname: Spinelli
authors.forename: Zubair M
authors.initials: ZM
authors.lastname: Ahmed
authors.forename: Inna A
authors.initials: IA
authors.lastname: Belyantseva
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
authors.forename: Peter G
authors.initials: PG
authors.lastname: Barr-Gillespie
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Frolenkov
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000378:metabolism; D006198:Hair Cells, Auditory / Q000502:physiology* / Q000648:ultrastructure; D006199:Hair Cells, Auditory, Inner / Q000648:ultrastructure; D040542:Mechanotransduction, Cellular; D051379:Mice; D008810:Mice, Inbred C57BL; D011498:Protein Precursors / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D059547:Stereocilia / Q000502:physiology / Q000648:ultrastructure
chemical_list: C418976:CDHR15 protein, mouse; D000070585:Cadherin Related Proteins; D015820:Cadherins; C499091:Cdh23 protein, mouse; D011498:Protein Precursors