Mutations in cadherin 23 affect tip links in zebrafish sensory hair cells

Nature. 2004 Apr 29;428(6986):955-9. doi: 10.1038/nature02484. Epub 2004 Mar 31.

Abstract

Hair cells have highly organized bundles of apical projections, or stereocilia, that are deflected by sound and movement. Displacement of stereocilia stretches linkages at the tips of stereocilia that are thought to gate mechanosensory channels. To identify the molecular machinery that mediates mechanotransduction in hair cells, zebrafish mutants were identified with defects in balance and hearing. In sputnik mutants, stereociliary bundles are splayed to various degrees, with individuals displaying reduced or absent mechanotransduction. Here we show that the defects in sputnik mutants are caused by mutations in cadherin 23 (cdh23). Mutations in Cdh23 also cause deafness and vestibular defects in mice and humans, and the protein is present in hair bundles. We show that zebrafish Cdh23 protein is concentrated near the tips of hair bundles, and that tip links are absent in homozygous sputnik(tc317e) larvae. Moreover, tip links are absent in larvae carrying weak alleles of cdh23 that affect mechanotransduction but not hair bundle integrity. We conclude that Cdh23 is an essential tip link component required for hair-cell mechanotransduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cilia / metabolism
  • Cilia / ultrastructure
  • Gene Expression Profiling
  • Hair Cells, Auditory / metabolism*
  • Hair Cells, Auditory / ultrastructure
  • Hearing / genetics
  • Hearing / physiology
  • Larva / genetics
  • Larva / physiology
  • Mechanotransduction, Cellular / genetics
  • Mechanotransduction, Cellular / physiology
  • Mutation / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Zebrafish / genetics
  • Zebrafish / physiology*
  • Zebrafish Proteins

Substances

  • Cadherins
  • RNA, Messenger
  • Zebrafish Proteins
  • cdh23 protein, zebrafish