Retinal degeneration in the pcd cerebellar mutant mouse. I. Light microscopic and autoradiographio analysis

Abstract

The Purkinje cell degeneration (pcd) mutant mouse rapidly loses cerebellar Purkinje cells between 3 and 5 weeks after birth and slowly loses retinal photoreceptor cells during the first year of life. In the present study, the retinal degeneration in the pcd mouse was analyzed by light microscopy and autoradiography throughout the first 15 months of age. By day 25 there is an abundance of pyknotic photoreceptor nuclei and many outer segments are clearly disorganized. Thereafter, as the photoreceptor cells are lost, their outer segments slowly become shorter and more variable in length; this slow change in length is explained by an almost proportional reduction in both rod outer segment renewal and disc shedding rates. At about 2 months of age, the rate of rod outer segment renewal is slightly less than half that in littermate controls, and the number of large phagosomes in pigment epithelial cells during the burst of disc shedding soon after light onset is one-half or less than that seen in littermate controls. Between 2 and 10.5 months of age, the retina in the inferior hemisphere of the eye shows substantially more-advanced photoreceptor degeneration than does the superior hemisphere, particularly in the far peripheral retina. A central-to-peripheral gradient of degeneration is conspicuous in the superior hemisphere; a similar but less obvious gradient of degeneration is also seen in the inferior hemisphere of the eye. Loss of photoreceptor cells and their synaptic terminals results in a predictable thinning of the outer synaptic layer. However, the inner nuclear layer shows no measurable thinning and the inner synaptic layer is reduced in thickness by only about 5-15%. Beginning at about 10 months of age, foci of thinned pigment epithelial cells are evident, and by 12 months there is some vascularization of the pigment epithelium by retinal capillaries.

Alterations in the balance of tubulin glycylation and glutamylation in photoreceptors leads to retinal degeneration

“…Using a knockout mouse model for the glycylase TTLL3, we demonstrate that changes in the levels of glycylation lead to hyperglutamylation, followed by progressive degeneration of the photoreceptors. This situation is comparable to that of the pcd mouse model, which has earlier been shown to develop retinal degeneration Blanks and Spee, 1992;LaVail et al, 1982). Our data demonstrate that both glycylation and glutamylation are enriched at the photoreceptor connecting cilium, and that they influence each other.…”

“…Strikingly, pcd mice also show progressive degeneration of photoreceptors, which starts at P15, when the first pyknotic nuclei can be observed in photoreceptors. Between 3 and 5 weeks of age, 50% of the photoreceptors are lost, and degeneration is complete after 1 year Chang et al, 2002;LaVail et al, 1982;Mullen and LaVail, 1975).…”

Morphological characterization of the retinal degeneration in three strains of mice carrying the rd-3 mutation

“…Such patterns of hypopigmentation, due to a variety of causes including but not limited to RPE cell dropout, have been seen in fundus photographs of most of the known murine inherited retinal degenerations~Hawes et al, 1999;Chang et al, 2002;Mehalow et al, 2003;Pang et al, 2005!. As we have reported here, several studies correlate areas of RPE cell thinning with the apposing and localized loss of photoreceptor cell bodies comprising the ONL~Caley et al, 1972;Sanyal & Bal, 1973;Sanyal et al, 1980;LaVail et al, 1982LaVail et al, , 1993Blanks et al, 1982;Messer et al, 1993!. As in other photoreceptor degenerations, Müller cells fill in space left by these dying photoreceptors. Though immunocytochemistry shows that there is some upregulation of GFAP in these cells, as has been seen in other retinal degenerations~Eisenfeld et al, 1984;Lewis et al, 1994!, we , there is an increase in apoptotic profiles though they are still restricted to the inner retinal layers.…”

Zebrafish Cytosolic Carboxypeptidases 1 and 5 Are Essential for Embryonic Development

“…CCP1 mRNA is most highly expressed in the zebrafish brain, consistent with expression patterns of CCP1 mRNA in the mouse and with the neuronal phenotypes of the pcd mutants (11). Our study indicated a smaller eye size in CCP1 and CCP5 morphants that could be related to photoreceptor degeneration, although this does not normally occur in the pcd mouse until relatively late in development (38,39). Finally, the broad expression of CCP1 mRNA at early developmental stages but viability of morphant embryos suggests partial redundancy of function.…”