RT Journal Article
SR Electronic
T1 Noddy, a Mouse Harboring a Missense Mutation in Protocadherin-15, Reveals the Impact of Disrupting a Critical Interaction Site between Tip-Link Cadherins in Inner Ear Hair Cells
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 4395
OP 4404
DO 10.1523/JNEUROSCI.4514-12.2013
VO 33
IS 10
A1 Ruishuang Geng
A1 Marcos Sotomayor
A1 Kimberly J. Kinder
A1 Suhasini R. Gopal
A1 John Gerka-Stuyt
A1 Daniel H.-C. Chen
A1 Rachel E. Hardisty-Hughes
A1 Greg Ball
A1 Andy Parker
A1 Rachelle Gaudet
A1 David Furness
A1 Steve D. Brown
A1 David P. Corey
A1 Kumar N. Alagramam
YR 2013
UL http://www.jneurosci.org/content/33/10/4395.abstract
AB In hair cells of the inner ear, sound or head movement increases tension in fine filaments termed tip links, which in turn convey force to mechanosensitive ion channels to open them. Tip links are formed by a tetramer of two cadherin proteins: protocadherin 15 (PCDH15) and cadherin 23 (CDH23), which have 11 and 27 extracellular cadherin (EC) repeats, respectively. Mutations in either protein cause inner ear disorders in mice and humans. We showed recently that these two cadherins bind tip-to-tip in a “handshake” mode that involves the EC1 and EC2 repeats of both proteins. However, a paucity of appropriate animal models has slowed our understanding both of the interaction and of how mutations of residues within the predicted interface compromise tip link integrity. Here, we present noddy, a new mouse model for hereditary deafness. Identified in a forward genetic screen, noddy homozygotes lack inner ear function. Mapping and sequencing showed that noddy mutant mice harbor an isoleucine-to-asparagine (I108N) mutation in the EC1 repeat of PCDH15. Residue I108 interacts with CDH23 EC2 in the handshake and its mutation impairs the interaction in vitro. The noddy mutation allowed us to determine the consequences of blocking the handshake in vivo: tip link formation and bundle morphology are disrupted, and mechanotransduction channels fail to remain open at rest. These results offer new insights into the interaction between PCDH15 and CDH23 and help explain the etiology of human deafness linked to mutations in the tip-link interface.