Photoreceptor Dysgenesis in Dystonin Mutant Mice

Abstract

Abstract: : Purpose: Development of the vertebrate retina is regulated by numerous extrinsic and intrinsic factors. Laminins in the extracellular matrix (ECM) provide environmental cues that are essential for proper retinal cell differentiation, morphology, and function. We are interested in identifying membrane associated receptors that mediate the stabilizing effects of laminins in the retina. Collagen XVII and bullous pemphigoid antigen 1 (BPAG-1) interact in hemidesmosomes, linking the ECM to the cytoskeleton in basal keratinocytes. We hypothesize that collagen XVII and dystonin, a neural isoform of BPAG-1, function in a similar way in the retina. We are testing this hypothesis using a dystonin mutant mouse. Methods: We have used standard histology, immunohistochemistry, and Western blot analysis to examine the expression and localization of dystonin and collagen XVII. Wild type and dystonia musculorum (dt) mice were examined during late stages of postnatal development. Confocal microscopy and deconvolution analysis provide high resolution 3-D reconstruction of photoreceptor synapses. Results: We previously demonstrated that dystonin and collagen XVII are expressed in the retina. Dystonin is expressed exclusively in the photoreceptors; with high levels in the outer segment and at the synaptic terminals. Collagen XVII is expressed in high levels in the synaptic terminals and outer segments of photoreceptors as well as in Muller cells. Here we demonstrate that a naturally-occurring mutation in the dystonin gene in the dystonia musculorum (dt) mouse is associated with a severe retinal phenotype. In mice lacking retinal expression of dystonin, we see a rapid and fast degeneration of photoreceptors; as early as P17, the ONL is reduced to a single row of photoreceptor cell bodies with no inner or outer segments. These cells do express a low level of rhodopsin immunoreactivity. To our knowledge this is the first demonstration of the retinal phenotype in this mouse and represents a new model for early onset degeneration. Conclusions: The expression of dystonin and collagen XVII in the retina and their structural role in the hemidesmosome suggest that they may be involved in photoreceptor morphogenesis. The degeneration of photoreceptors observed in the dt mice suggests that dystonin is critical for development and maintenance of photoreceptors.

Keywords: photoreceptors • degenerations/dystrophies • cytoskeleton