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Retinal ganglion cell degeneration is topological but not cell type specific in DBA/2J mice.

Jakobs TC, Libby RT, Ben Y, John SW, Masland RH - J. Cell Biol. (2005)

Bottom Line: Regions of cell death or survival radiated from the optic nerve head in fan-shaped sectors.Collectively, the data suggest axon damage at the optic nerve head as an early lesion, and damage to axon bundles would cause this pattern of degeneration.However, the architecture of the mouse eye seems to preclude a commonly postulated source of mechanical damage within the nerve head.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02114.

ABSTRACT
Using a variety of double and triple labeling techniques, we have reevaluated the death of retinal neurons in a mouse model of hereditary glaucoma. Cell-specific markers and total neuron counts revealed no cell loss in any retinal neurons other than the ganglion cells. Within the limits of our ability to define cell types, no group of ganglion cells was especially vulnerable or resistant to degeneration. Retrograde labeling and neurofilament staining showed that axonal atrophy, dendritic remodeling, and somal shrinkage (at least of the largest cell types) precedes ganglion cell death in this glaucoma model. Regions of cell death or survival radiated from the optic nerve head in fan-shaped sectors. Collectively, the data suggest axon damage at the optic nerve head as an early lesion, and damage to axon bundles would cause this pattern of degeneration. However, the architecture of the mouse eye seems to preclude a commonly postulated source of mechanical damage within the nerve head.

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Sectors of backfilled cells correspond to sectors with relatively many axons. (A) Low-power view of a retina with moderate glaucoma. The whole mount was stained for the neurofilament marker SMI32, which labels axons and a population of large ganglion cells (green). The outlined squares (fields 1–4) and the outlined irregular box indicate the positions of the higher power insets and of the area in B and C, respectively. The axons and large cell bodies of SMI32+ ganglion cells are shown in green. The arrows in field 1 point to SMI32+ cells. ChAT+ (starburst) amacrine cells are labeled in red, and the cell nuclei are stained with TOPRO (blue). Note the marked difference in the numbers of axons that can be seen traversing the fields. The cell densities in these fields also vary between 7,728 and 7,744 cells/mm2 in fields 1 and 2 and between 6,352 and 5,936 cells/mm2 in fields 3 and 4, respectively. Bar, 100 μm. (B) The irregular boxed area from A (stained for SMI32) at higher resolution. (C) The same area as in B, but showing rhodamine-dextran backfill. Individual cell bodies are barely distinguishable as red dots at this magnification. Areas with high numbers of backfilled cells correspond to areas with relatively high numbers of persisting SMI32+ axons. Bar, 500 μm.
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fig6: Sectors of backfilled cells correspond to sectors with relatively many axons. (A) Low-power view of a retina with moderate glaucoma. The whole mount was stained for the neurofilament marker SMI32, which labels axons and a population of large ganglion cells (green). The outlined squares (fields 1–4) and the outlined irregular box indicate the positions of the higher power insets and of the area in B and C, respectively. The axons and large cell bodies of SMI32+ ganglion cells are shown in green. The arrows in field 1 point to SMI32+ cells. ChAT+ (starburst) amacrine cells are labeled in red, and the cell nuclei are stained with TOPRO (blue). Note the marked difference in the numbers of axons that can be seen traversing the fields. The cell densities in these fields also vary between 7,728 and 7,744 cells/mm2 in fields 1 and 2 and between 6,352 and 5,936 cells/mm2 in fields 3 and 4, respectively. Bar, 100 μm. (B) The irregular boxed area from A (stained for SMI32) at higher resolution. (C) The same area as in B, but showing rhodamine-dextran backfill. Individual cell bodies are barely distinguishable as red dots at this magnification. Areas with high numbers of backfilled cells correspond to areas with relatively high numbers of persisting SMI32+ axons. Bar, 500 μm.

Mentions: The distribution of the retrogradely labeled cells was unexpected. In normal retinas (C57BL/6J) and in the retina from the young DBA/2J animal, large contiguous parts, usually amounting to ≥50% of the total area, contain labeled cells (the entire retina is not covered because our injections into the superior colliculus do not cover the whole projection field of retinal ganglion cells). In the glaucoma retinas, we found sectors of brightly labeled cells interrupted by sectors that contained no or only very few labeled cells. Fig. 5 shows four examples, with A showing an unaffected retina and B, C, and D showing increasing severity. This result cannot be explained by the injection technique, as the fibers in the superior colliculus are not arranged in this manner, and in normal animals fan-shaped labeling of ganglion cells by retrograde transport is never observed. The areas of backfilled cells correspond to areas where the axon bundles are relatively well preserved, whereas the unlabeled sectors are also denuded of axons (Fig. 6).


Retinal ganglion cell degeneration is topological but not cell type specific in DBA/2J mice.

Jakobs TC, Libby RT, Ben Y, John SW, Masland RH - J. Cell Biol. (2005)

Sectors of backfilled cells correspond to sectors with relatively many axons. (A) Low-power view of a retina with moderate glaucoma. The whole mount was stained for the neurofilament marker SMI32, which labels axons and a population of large ganglion cells (green). The outlined squares (fields 1–4) and the outlined irregular box indicate the positions of the higher power insets and of the area in B and C, respectively. The axons and large cell bodies of SMI32+ ganglion cells are shown in green. The arrows in field 1 point to SMI32+ cells. ChAT+ (starburst) amacrine cells are labeled in red, and the cell nuclei are stained with TOPRO (blue). Note the marked difference in the numbers of axons that can be seen traversing the fields. The cell densities in these fields also vary between 7,728 and 7,744 cells/mm2 in fields 1 and 2 and between 6,352 and 5,936 cells/mm2 in fields 3 and 4, respectively. Bar, 100 μm. (B) The irregular boxed area from A (stained for SMI32) at higher resolution. (C) The same area as in B, but showing rhodamine-dextran backfill. Individual cell bodies are barely distinguishable as red dots at this magnification. Areas with high numbers of backfilled cells correspond to areas with relatively high numbers of persisting SMI32+ axons. Bar, 500 μm.
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Related In: Results  -  Collection

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fig6: Sectors of backfilled cells correspond to sectors with relatively many axons. (A) Low-power view of a retina with moderate glaucoma. The whole mount was stained for the neurofilament marker SMI32, which labels axons and a population of large ganglion cells (green). The outlined squares (fields 1–4) and the outlined irregular box indicate the positions of the higher power insets and of the area in B and C, respectively. The axons and large cell bodies of SMI32+ ganglion cells are shown in green. The arrows in field 1 point to SMI32+ cells. ChAT+ (starburst) amacrine cells are labeled in red, and the cell nuclei are stained with TOPRO (blue). Note the marked difference in the numbers of axons that can be seen traversing the fields. The cell densities in these fields also vary between 7,728 and 7,744 cells/mm2 in fields 1 and 2 and between 6,352 and 5,936 cells/mm2 in fields 3 and 4, respectively. Bar, 100 μm. (B) The irregular boxed area from A (stained for SMI32) at higher resolution. (C) The same area as in B, but showing rhodamine-dextran backfill. Individual cell bodies are barely distinguishable as red dots at this magnification. Areas with high numbers of backfilled cells correspond to areas with relatively high numbers of persisting SMI32+ axons. Bar, 500 μm.
Mentions: The distribution of the retrogradely labeled cells was unexpected. In normal retinas (C57BL/6J) and in the retina from the young DBA/2J animal, large contiguous parts, usually amounting to ≥50% of the total area, contain labeled cells (the entire retina is not covered because our injections into the superior colliculus do not cover the whole projection field of retinal ganglion cells). In the glaucoma retinas, we found sectors of brightly labeled cells interrupted by sectors that contained no or only very few labeled cells. Fig. 5 shows four examples, with A showing an unaffected retina and B, C, and D showing increasing severity. This result cannot be explained by the injection technique, as the fibers in the superior colliculus are not arranged in this manner, and in normal animals fan-shaped labeling of ganglion cells by retrograde transport is never observed. The areas of backfilled cells correspond to areas where the axon bundles are relatively well preserved, whereas the unlabeled sectors are also denuded of axons (Fig. 6).

Bottom Line: Regions of cell death or survival radiated from the optic nerve head in fan-shaped sectors.Collectively, the data suggest axon damage at the optic nerve head as an early lesion, and damage to axon bundles would cause this pattern of degeneration.However, the architecture of the mouse eye seems to preclude a commonly postulated source of mechanical damage within the nerve head.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02114.

ABSTRACT
Using a variety of double and triple labeling techniques, we have reevaluated the death of retinal neurons in a mouse model of hereditary glaucoma. Cell-specific markers and total neuron counts revealed no cell loss in any retinal neurons other than the ganglion cells. Within the limits of our ability to define cell types, no group of ganglion cells was especially vulnerable or resistant to degeneration. Retrograde labeling and neurofilament staining showed that axonal atrophy, dendritic remodeling, and somal shrinkage (at least of the largest cell types) precedes ganglion cell death in this glaucoma model. Regions of cell death or survival radiated from the optic nerve head in fan-shaped sectors. Collectively, the data suggest axon damage at the optic nerve head as an early lesion, and damage to axon bundles would cause this pattern of degeneration. However, the architecture of the mouse eye seems to preclude a commonly postulated source of mechanical damage within the nerve head.

Show MeSH
Related in: MedlinePlus