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X. Sun, B. Pawlyk, M. Adamian, N. Michaud, O.V. Bulgakov, T. Li; Functional and Structural Deficits of Cone Photoreceptors in Mice Lacking PCDH15, a Protein Encoded by the Ush1F Gene . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5770.
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© ARVO (1962-2015); The Authors (2016-present)
Usher syndrome type 1 is characterized by visual defects due to photoreceptor degeneration, congenital hearing loss and vestibular dysfunction. One of the human genes known to be involved in Usher syndrome type 1, USH1F, encodes protocadherin 15 (PCDH15). Spontaneous mutations in murine Ush1F gene lead to profound inner ear dysfunction, but a retinal defect has so far evaded detection. This study was carried out to determine the localization of PCDH15 in the retina and to determine if there are any structural and functional defects in photoreceptors of the PCDH15–deficient mice.
Polyclonal antibodies targeting the N– and C–terminal regions of PCDH15 were developed. Subcellular localization of PCDH15 in murine and human photoreceptors was determined by immunofluorescence and immunoelectron microscopy, with PCDH15–deficient mice as negative controls. A potential dysfunction of retinal photoreceptors in the mutant mice was assessed by dark and light–adapted electroretinograms (ERG). PCDH15–deficient and WT mice aged 2 to 19 months were evaluated. Retinal cell morphology was assessed by light and electron microscopy.
PCDH15 is expressed in both rod and cone photoreceptors, and is localized in a region between the inner and outer segments. In mice, PCDH15 appears to be expressed at a much higher level in cones than in rods, whereas in humans, PCDH15 appears comparably abundant in both rods and cones. Combined double–staining immunofluorescence and immunoEM data suggest PCDH15 is localized on the apical inner segment membranes. ERG analyses show an age–dependent decline in cone ERG amplitude. Consistent with this, cone photoreceptors show an abnormal morphology at the apical inner segment region, with aberrant membranous profiles present within the inner segments.
PCDH15 is enriched at the apical inner segment plasma membrane of photoreceptors. PCDH15–deficiency in mice leads to functional and structural deficits primarily in cone photoreceptors, which is consistent with its predominant expression in cones. Thus, mice lacking PCDH15 exhibit both hearing and visual loss and, as such, are a model for human Usher syndrome type 1.
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