Morphological and physiological consequences of the selective elimination of rod photoreceptors in transgenic mice

We have produced transgenic mice (rdta mice) that express the gene for an attenuated diphtheria toxin under the control of a portion of the rhodopsin promotor. Morphologically, expression of this transgene results in the elimination of the majority of cell bodies in the outer nuclear layer (ONL) of the retina. This cell loss is evident as early as postnatal day 7 (P7), which corresponds closely to the onset of expression of rhodopsin in the mouse retina that occurs about P5. Reverse transcription-PCR (RT-PCR) analysis of mRNA from the retinae of rdta mice shows that the level of rhodopsin mRNA is reduced by 50% as early as P14 and, by P28, has declined to approximately 15% of that in the retinae of control mice. Electroretinographic recordings from the dark-adapted rdta mice at P17 reveal that their retinae do not generate any rod-mediated signals. The majority of the cell bodies that persist in the ONL of the rdta retinae have the morphological features of cone photoreceptors, although these cells never develop normal inner and outer segments. To confirm that the surviving cells are cones we crossed the rdta mice to a different line of transgenic mice that express the E. coli beta-galactosidase (lacZ positive) reporter gene in all cone photoreceptors. In retinae from mice that inherit both transgenes, nearly every cell that remains in the ONL expresses lacZ and, thus, is a cone. This finding also is consistent with RT-PCR analyses, which show that cone opsin mRNAs persist in the retinae of our rdta mice at ages when rhodopsin mRNA is significantly reduced. Electroretinograms can be obtained from the rdta mice under conditions that saturate the rod response and, thus, providing evidence that the cones that remain are functional, even though they lack inner and outer segments. Finally, we have examined the inner nuclear layer for changes that result from rod photoreceptor ablation. We show that, while the elimination of the rod photoreceptors has little or no effect on the morphology of the post-synaptic neurons, this deletion does alter their laminar position. (C) 1996 Academic Press Limited