The goal of this application is to analyze in detail cellular mechanisms underlying the development of form and function in the visual and olfactory sensory systems. Our approach is to precisely ablate specific cell types in early development by targeting the expression of diptheria toxin in transgenic mice. Promoters for polypeptides expressed exclusively in cells of the eye, nose, and forebrain will be joined in vitro to the diptheria toxin coding sequence. This strategy has already been used successfully with the alpha-crystallin promoter to generate seven lines of mice which completely lack eye lens tissue as adults. We propose here to examine the embryonic development of these mice. New transgenic lines will be developed in which the crystallin promoter is linked to the histochemical marker galactosidase. These, the crystallin/diptheria toxin mice, and also aggregation mosaic animals will all be examined to determine (a) if lens structures exist transiently during development in the crystallin/diptheria toxin mice and (b) if the development of the ciliary epithelium and ciliary body require the presence of a lens. In the second major project, the primary neurons of the olfactory epithelium will be ablated by targeting with the promoter for the polypeptide olfactory marker protein. In these mice cell populations within the epithelium will be examined to determine lineage relationships. In addition the effects of this sensory deprivation on the development of the olfactory bulb and of selected CANS regions will be determined. The third set of mice to be produced will lack rod cells of the neural retina by targeting ablation using the rod opsin promoter. These mice will be used to determine (a) cell lineage relationships in the eye, (b) the extent to which bipolar cell ramification patterns are dependent on rod input and (c) the identity of pineal cells which express rod opsin. In summary, these studies will (1) evaluate the potential of the targeted ablation method for analysis of neural development and (2) establish lineage relationships in the eye and nasal epithelium and determine cell and tissue dependencies and inter-relationships during the development of the eye, nose, and brain. The studies will also provide murine model systems for specific developmental defects such s retinitis pigmentosa.
| Key, B; Liu, L; Potter, S S et al. (1992) Lens structures exist transiently in development of transgenic mice carrying an alpha-crystallin-diphtheria toxin hybrid gene. Exp Eye Res 55:357-67 |
