A core cochlear phenotype in USH1 mouse mutants implicates fibrous links of the hair bundle in its cohesion, orientation and differential growth

Abstract

*The planar polarity and staircase-like pattern of the hair bundle are essential to the mechanoelectrical transduction function of inner ear sensory cells. Mutations in genes encoding myosin VIIa, harmonin, cadherin 23, protocadherin 15 or sans cause Usher syndrome type I (USH1, characterized by congenital deafness, vestibular dysfunction and retinitis pigmentosa leading to blindness) in humans and hair bundle disorganization in mice. Whether the USH1 proteins are involved in common hair bundle morphogenetic processes is unknown. Here, we show that mouse models for the five USH1 genetic forms share hair bundle morphological defects. Hair bundle fragmentation and misorientation (25-52° mean kinociliary deviation, depending on the mutant) were detected as early as embryonic day 17. Abnormal differential elongation of stereocilia rows occurred in the first postnatal days. In the emerging hair bundles, myosin VIIa, the actin-binding submembrane protein harmonin-b, and the interstereocilia-kinocilium lateral link components cadherin 23 and protocadherin 15, all concentrated at stereocilia tips, in accordance with their known in vitro interactions. Soon after birth, harmonin-b switched from the tip of the stereocilia to the upper end of the tip link, which also comprises cadherin 23 and protocadherin 15. This positional change did not occur in mice deficient for cadherin 23 or protocadherin 15. We suggest that tension forces applied to the early lateral links and to the tip link, both of which can be anchored to actin filaments via harmonin-b, play a key role in hair bundle cohesion and proper orientation for the former, and in stereociliary elongation for the latter.

Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia

“…The direct in vitro interactions between the five USH1 proteins (2,(12)(13)(14)(15)(16) and the colocalization of cadherin-23, protocadherin-15, myosin VIIa, and harmonin in the growing hair bundle, along with the common early morphological defect in cochlear hair bundles of mouse mutants defective for any USH1 gene (17), suggest that USH1 proteins cooperate in hair bundle development. It has been proposed that harmonin-b anchors transient fibrous lateral links to the stereocilia actin filaments and that myosin VIIa creates tension on these links (2,16), but the role played by sans is still unknown.…”

A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells

“…1 A) (16)(17)(18)(19)(20), and their cytoplasmic domains bind to protein complexes containing harmonin, MYO7A, and sans (21)(22)(23)(24)(25). Predicted null mutations in murine USH1 genes cause defects in hair bundle development (24,(26)(27)(28)(29)(30)(31)(32)(33)(34), suggesting that USH1 proteins form transmembrane complexes that regulate hair bundle morphogenesis. Failure of these complexes likely causes USH1.…”

Listen to your gut: Using adhesion to shape the surface of functionally diverse epithelia

“…34,35 Consistent with studies on the IMAC, formation of the tip-link complex also appears to be critical for hair bundle organization. 36 Thus, a conserved apical adhesion complex consisting of 2 cadherin family members, 2 scaffolding proteins, and a myosin motor, physically connects and organizes protrusions in apical specializations with entirely distinct morphologies and physiological functions ( Table 1, Fig. 2B).…”