The protein neural retina leucine zipper (Nrl) is a basic motif-leucine zipper transcription factor that is preferentially expressed in rod photoreceptors. It acts synergistically with Crx to regulate rhodopsin transcription. Missense mutations in human NRL have been associated with autosomal dominant retinitis pigmentosa. Here we report that deletion of Nrl in mice results in the complete loss of rod function and super-normal cone function, mediated by S cones. The photoreceptors in the Nrl-/- retina have cone-like nuclear morphology and short, sparse outer segments with abnormal disks. Analysis of retinal gene expression confirms the apparent functional transformation of rods into S cones in the Nrl-/- retina. On the basis of these findings, we postulate that Nrl acts as a 'molecular switch' during rod-cell development by directly modulating rod-specific genes while simultaneously inhibiting the S-cone pathway through the activation of Nr2e3.

The RS-KO mouse mimics structural features of human X-linked juvenile retinoschisis with dissection through, and disorganization of, multiple retinal layers. The Rs1h-KO functional deficit results in an electronegative ERG waveform that is characteristic of human retinoschisis disease and that implicates a synaptic transmission deficit in the absence of retinoschisin protein. Replacement therapy by supplementing normal Rs1h protein in the adult Rs1h-KO mouse restored the normal ERG configuration. This indicates that gene therapy is a viable strategy of therapeutic intervention even in the postdevelopmental adult stage of XLRS disease.

The ERG of the Rs1h-KO mouse at early ages reflects disruption of photoreceptor and second-order neuron function. In mid to late ages, the ERG decline reflects primarily photoreceptor degeneration. The Rs1h-KO mouse is consistent with human clinical X-linked juvenile retinoschisis (XLRS) in showing schisis cavities, which affect primarily the b-wave, the regression of schisis cavities at older ages, and a considerable range in phenotypic severity across individuals. This mouse model also indicates the critical roll of RS-protein in photoreceptor survival consistent with decreased a-waves in some patients with XLRS. Long-term rescue of retinal morphology and function by AAV-Rs1h gene transfer may provide a basis for considering intervention in the homologous human XLRS condition.