Mouse models for CRB1-associated human diseases

Mouse models for CRB1-associated human diseases have been described by two groups. Dr. Mehalow and coworkers at the Jackson Laboratories described the identification of a naturally occurring mouse mutant, called rd8, in which a mutation in the mouse Crb1 gene gives rise to a truncated secreted protein that lacks the intracellular domain, the transmembrane domain, and four of the C-terminal epidermal growth factor domains. The retinas of these mice show a typical white-spotting phenotype and occasional retinal folds and pseudorosettes at foci in the retina (Mehalow et al. 2003). In these folds, the photoreceptor cell layer curves inwardly to form omega-shaped structures which protrude into the nuclear and neural cell layers. The folds correlate with the white spotting upon fundus imaging. After 3 months, the inner and outer segments of the photoreceptors shorten and gradually show a disorganisation.

Simultaneously, a Crb1 knock-out was made by the consortium by replacing part of the CRB1 gene in such a way that no Crb1 protein is made (van de Pavert et al. 2004). The Crb1 knock-out retinas showed focal migration of photoreceptors into the subretinal space and outer plexiform layer, and formation of half-rosettes of photoreceptors besides the photoreceptor layer (Figure 5), suggesting that Crb1 in the outer limiting membrane plays an important regulatory role in the maintenance of adhesion between photoreceptors and Müller cells. Retinal disorganization was accelerated by exposure to low levels of light and preceded focal degeneration of the inner and outer neural retina. These mice will be used to analyse the phenotype in more detail and form the basis for experiments aimed at the rescue of the phenotype. 

Currently a Crb2-knockout and a Crb3-knockout mice are being produced by the Crumbs consortium.