This proposal requests funding for examination of the hypotheses that (1) tyrosinase activity in the embryonic eye results in the formation of developmental signals, that (2) these signals, perhaps amines, direct the generation of ganglion cells in the embryonic eye and that (3) the signals made through the activity of tyrosinase are transient and are made before tyrosinase switches to the synthesis of melanin in the pigment epithelium. The effects of amines on spatiotemporal features of neurogenesis would in turn lead to designation of the crossed and uncrossed projection of retinal ganglion cells. Our studies will focus on two lines of mice that are genetically identical except for a mutation at the tyrosinase locus. One line is pigmented (C57B16 Tyr+), the other, the albino (C57B16 Tyrc2j) carries a point mutation in the gene that codes for tyrosinase. The albino is known to have aberrant ganglion cell projections with the ipsilateral pathway reduced by half. Lack of functional tyrosinase in the albino is also correlated with changes in the timing of generation of retinal ganglion cells. Using histological and biochemical techniques, we will determine whether catechol or other amines are formed transiently in the developing eye, as is the case in peripheral tissues. We will test whether these substances are formed as a consequence of tyrosinase activity, again, as occurs in peripheral tissues. We will examine developing eye to see if there is a switch from the formation of developmental signals by tyrosinase to the formation of melanin, as also may be the case in peripheral tissues. We will correlate these events with the birth and differentiation of retinal ganglion cells. If we do find candidates for developmental signals for generation of retinal ganglion cells, we will test their effectiveness as signals in retina in vitro, and in vivo using tissues from albino mice including the OA1 knockout in which a G protein coupled receptor within melanosomes is mutated. Ultimately, if such signals deriving from tyrosinase-driven pathway unrelated to melanin production, are found, this research will open doors to therapeutic intervention in individuals carrying the OA1 gene.
| Takemoto, Dolores J; Harris, Richard; Brightman, Al et al. (2004) Normalization of lens protein kinase Cgamma in galactosemic dogs by a novel aldose reductase inhibitor. Vet Ophthalmol 7:163-7 |
