Severe retinal degeneration associated with disruption of semaphorin 4A

Abstract

Abstract: : Purpose: To characterize retinal degeneration in mice lacking transmembrane Semaphorin 4A (Sema4A) Methods: Lexicon employs a phenotype–driven screen to identify therapeutically relevant physiology in genetically altered mice. A strategy based on high–throughput retroviral gene–trapping in embryonic stem (ES) cells has produced mutations in over 60% of genes comprising the mouse genome. An ES cell clone with a retroviral insertion in the semaphorin 4A (Sema4A) gene was used to generate mice lacking this transmembrane semaphorin. Fundus exam and angiography were performed on adult mice to identify clinical phenotypes. Electron microscopy and immunohistochemistry using cell type specific markers were used to characterize retinal anatomy at different developmental ages. In situ hybridization using sema4A–specific probes was used to localize expression of this gene in the developing and adult eye. Results: Fundus exam at 14 weeks of age revealed severe retinal degeneration, attenuated retinal vessels and de–pigmentation in mice lacking Sema4A. At this age, the outer nuclear layer is reduced to a single row of photoreceptor cells and the outer plexiform layer is thin and disorganized. Developmental studies of mice deficient in Sema4A identified an abnormal development of photoreceptor outer segments. Sema4A is expressed in the inner retina and retina pigment epithelium (RPE) during the time at which outer segments form intimate contacts with apical microvilli of RPE cells. Conclusions: These findings identify a previously unknown function of Sema4A in the developing visual system and provide a useful model to understand cell–cell interactions that occur between photoreceptors and the RPE.

Keywords: degenerations/dystrophies • retina: distal (photoreceptors, horizontal cells, bipolar cells) • retinal pigment epithelium