Lineage studies have shown that retinal cells, as well as many other cells in the vertebrate nervous system, are born pluripotent Culture studies have demonstrated that cellular interactions can drive these pluripotent cells toward particular fates. This is a proposal to investigate the nature of these inductive pathways. For Xenopus photoreceptors, there are two temporally distinct inductive events. The first is necessary to turn on some antigens expressed in both rods and cones, and the second one induces cells to express rod specific markers. Two general schemes of determination are consistent with these separate inductions. In one a single cell is exposed to a series of inductive events that increasingly restrict its fate; in the other, single distinct interactions induce the different cell types.
One aim of this proposal is to distinguish between these two possibilities by a using a combination of mixed cell cultures and immunocytochemical tagging. Another main objective of this proposal is to test explicitly whether similar inductive schemes are used for other cell types in the retina. There is an evolutionarily conserved order in retinal histogenesis in vertebrates, and we will investigate the possibilities that this occurs because inductive signals arise in a particular sequence, or because cells change their competence to respond to inductive signals. Changes in competence will be assayed by removing labeled cells from the retina at different stages of development, exposing them to the same inductive cues, and examining the appearance of particular cell types among the labeled cells. The last major goal of this proposal is to examine the role of particular growth factors in retinal development in vivo, by misexpression of dominant-activated and dominant- negative forms of growth factor receptors m vivo, and examining retinal cell development immunohistochemically. The long term objectives of this proposal are to understand the cascade of cell determination in the vertebrate nervous system at a cellular and a molecular level. One has to understand who induces who, what the signals are, and what the receptors are. This proposal paves the way for a better understanding of the order of cellular genesis in the nervous system, in particular a working model for the generation of organized cellular complexity from a specific sequence of inductive events. The retina is a highly accessible and well studied part of the vertebrate central nervous system and will serve well as an experimental system for future work of this sort. The basic understanding of how cells are determined in the retina, and the capability of controlling these inductive events in culture and in vivo, may have implications for retinal regeneration after surgery or injury. This work may also have applications in understanding the embryonic malformations of the retina.
| Chang, W S; Harris, W A (1998) Sequential genesis and determination of cone and rod photoreceptors in Xenopus. J Neurobiol 35:227-44 |
| Hirsch, N; Harris, W A (1997) Xenopus Pax-6 and retinal development. J Neurobiol 32:45-61 |
| Kanekar, S; Perron, M; Dorsky, R et al. (1997) Xath5 participates in a network of bHLH genes in the developing Xenopus retina. Neuron 19:981-94 |
