Extrinsic modulation of retinal ganglion cell projections: Analysis of thealbino mutation in pigmentation mosaic mice

Tyrosinase is a key enzyme involved in the synthesis of melanin in the reti nal pigment epithelium (RPE). Mice that are homozygous for the albino allel e at the tyrosinase locus have fewer retinal ganglion cells with uncrossed projections at the optic chiasm. To determine the site of the albino gene a ction we studied the projections of retinal ganglion cells in two types of pigmentation mosaic mice. First, we generated mosaic mice that contain a tr anslocated allele of the wild-type tyrosinase on one X chromosome but that also have the lacZ reporter transgene on the opposite X chromosome. In thes e lacZ/tyrosinase mice, which are homozygous for the albino allele on chrom osome 7, X-inactivation ensures that tyrosinase cannot be functional within 50% of the retinal ganglion cells and that these individual cells can be i dentified by their expression of the lacZ reporter gene product, beta-galac tosidase. The proportion of uncrossed retinal ganglion cells expressing bet a-galactosidase was found to be identical to the proportion that did not ex press it, indicating that the albino mutation associated with axonal behavi or at the optic chiasm must affect ganglion cells in a cell-extrinsic manne r. Second, to determine whether the RPE is the source of the extrinsic sign al, we generated aggregation chimeras between pigmented and albino mice. Zn these mosaic mice, the extent of the uncrossed projection corresponded wit h the amount of pigmented cells within the RPE, but did not correspond with the genotypes of neural retinal cells. These studies demonstrate that the albino mutation acts indirectly upon retinal ganglion cells, which in turn respond by making axonal guidance errors at the optic chiasm. (C) 1999 Acad emic Press.