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Fig. 4. Distributions of USH1 proteins in developing and adult hair cells throughout life, their spatial and temporal subcellular distribution vary for each molecule. Green arrows indicate the presence of a USH1 protein in the stereocilia. Myosin VIIa (Hasson et al., 1997 ) and protocadherin 15 (Ahmed et al., 2003) are present along the entire length of the stereocilia. The precise distribution of harmonin in the stereocilia at the postnatal stages remains to be established. Notice that, at P30, cadherin 23 disappears from the stereocilia and appears to move to the pericuticular necklace (Lagziel et al., 2005; Michel et al., 2005). Sans is no longer present in the stereocilia (Adato et al., 2005). Arrowheads refer to the stage when first signs of hair bundle anomalies have been reported in USH1 mouse mutants; E18 in shaker-1 (Self et al., 1998) and waltzer (Holme and Steel, 2002) mutants, and P0 in Ames waltzer (Washington et al., 2005). In Jackson shaker and deaf-circler mutants, the hair bundle disorganisation has been reported only from P10 (Kitamura et al., 1992), and P21 (Johnson et al., 2003), respectively.
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-helical domain, followed by two large repeats, each containing a myosin tail homology 4 (MyTH4) and a 4.1, Ezrin, Radixin, Moesin (FERM)-like domain. These are separated by a poorly conserved Src homology 3 (SH3) domain. Positions of the spliced exon 25 (ex 25) and 34 (ex 34) are indicated. There are three classes of harmonin isoform, depending on the presence of two or three PDZ domains and the presence or absence of a second coiled-coil (CC) domain associated with a proline-, serine- and threonine-rich (PST) domain. The largest cadherin 23 and protocadherin 15 isoforms have 27 extracellular cadherin (EC) repeats and 11 EC repeats, respectively. Sans is composed of three ankyrin (ANK)-like repeats and a sterile alpha motif (SAM) domain. (B) Summary of the direct interactions between USH1 proteins. The domains involved in each interaction are indicated by arrows. Harmonin is able to bind to any of the other USH1 proteins. The cytoplasmic regions of cadherin 23a isoforms containing or lacking the exon 68-encoded peptide (ex 68 in A) preferentially bind to the harmonin PDZ1 or PDZ2 domain, respectively. Harmonin can bind to the cytoplasmic region of protocadherin 15 through its first two PDZ domains. It can also bind to the myosin VIIa tail through a PDZ1–C-terminal-MyTH4-FERM domain interaction. Harmonin can also bind to Sans through a PDZ1-SAM region interaction. Finally, the Sans central region can bind to the myosin VIIa N-terminal MyTH4-FERM domain. Harmonin (not shown) and Sans can also form homodimers.
