Molecular mechanism of subtype specific death of retinal ganglion cells induced by different stimuli.

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It has been well known that there are several subtypes of retinal ganglion cells (RGCs) discriminated by their soma sizes, dendrite morphology and electrophysiological properties. After optic nerve transaction, smaller types of RGCs die predominantly. By contrast, larger types of RGCs die earlier in glaucoma than the smaller type. However, the molecular mechanisms of subtype specific RGC death are not known yet.In this project, we first tried to determine which type of BH3-only protein genes are induced by optic nerve transaction and glaucoma model by quantitative polymerase chain reaction (PCR). One day after the optic nerve transaction, only a subset of BH3-only protein messenger RNA (mRNA) were induced. Most of the BH3-only protein genes examined were not changed statistically by optic nerve transaction. By contrast, intra-vitreal injection of N-methyl-D-aspartic acid, a glaucoma model, induced different type of BH3-only protein gene.Next, Bim protein expression was investigated on the optic nerve transected rat and ferret retinas by immunohistochemistry. In ferret retina, morphological and physiological properties of RGCs and their correlations are well studied. In rat retina, anti-Bim antibody labeled RGCs after optic nerve transection. On the flatmount retina, we tried to determine which type of RGCs predominantly expressing Bim protein. Soma size distribution of Bim expressing cells was different from that of all the surviving RGCs. This is the first report that Bim was induced predominantly in subtypes of RGCs. In ferret retina, Bim expressing RGCs were also investigated on the flatmount retina. We also demonstrated that Bim was expressing selectively in subtypes of RGC. These results strongly suggested that Bim and other BH3-only proteins contribute to subtype specific RGC death on different death inducing stimuli.