Usher syndrome Type 1-associated gene, pcdh15b, is required for photoreceptor structural integrity in zebrafish

Blindness associated with Usher Syndrome Type 1 (USH1) is typically characterized as rod photoreceptor degeneration, followed by secondary loss of cones. The mechanisms leading to blindness are unknown since most genetic mouse models only recapitulate auditory defects. We generated zebrafish mutants for one of the USH1 proteins, protocadherin-15b (pcdh15b), a putative cell adhesion molecule. Zebrafish pcdh15 is expressed exclusively in photoreceptors within calyceal processes (CPs), at the base of the outer segment (OS), and within the synapse. In our mutants, rod and cone photoreceptor integrity is compromised with early and progressively worsening abnormal OS disc growth and detachment, in part due to weakening CP contacts. These effects were attenuated or exacerbated by growth in dark and bright light conditions, respectively. We also describe novel evidence for structural defects in synapses of pcdh15 mutant photoreceptors. Cell death does not accompany these defects at early stages, suggesting that photoreceptor structural defects, rather than overt cell loss, may underlie vision deficits. Thus, we present the first genetic animal model of a pcdh15-associated retinopathy that can be used to understand the etiology of blindness in USH1.