Synaptogenesis and outer segment formation are perturbed in the neural retina of Crx mutant mice

A Crx mutant strain of mice was created to serve as a model for LCA and to provide more insight into Crx's function. In this study, an ultrastructural analysis of the developing retina in Crx mutant mice was performed. Outer segment morphogenesis was found to be blocked at the elongation stage, leading to a failure in production of the phototransduction apparatus. Further, Crx-/- photoreceptors demonstrated severely abnormal synaptic endings in the outer plexiform layer.This is the first report of a synaptogenesis defect in an animal model for LCA. These data confirm the essential role this gene plays in multiple aspects of photoreceptor development and extend our understanding of the basic pathology of LCA.Photoreceptor cells play a primary role in vision by capturing light energy and converting it into neural stimuli. These sensory neurons are a shared element in all organisms capable of sensing light. In humans, genetic diseases of the eye are common and the primary site of disease is most frequently photoreceptors (for review see [1-3]).Photoreceptors have been well studied, particularly with respect to the biochemistry and physiology of phototransduction. Insight into the development of vertebrate photoreceptors, however, has lagged behind our understanding of function. Only recently have the first molecular mechanisms regulating photoreceptor development been identified (for review see, [2,4]). Crx (cone-rod homeobox) is an otx-family homeobox gene expressed predominantly in photoreceptors, from early in their development through to the adult ages [5-7]. Crx gene expression is critically dependent upon Otx2, another member of the same homeobox family which is expressed in early photoreceptor cells [8]. In rod photoreceptors, Crx appears to work in concert with Nrl, a leucine zipper protein that is also restricted in its expression in the retina to rod photoreceptors [9]. Many photoreceptor-specific genes have putative Crx-binding elements in their regulatory r