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Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma.

Howell GR, Libby RT, Jakobs TC, Smith RS, Phalan FC, Barter JW, Barbay JM, Marchant JK, Mahesh N, Porciatti V, Whitmore AV, Masland RH, John SW - J. Cell Biol. (2007)

Bottom Line: We show that proximal axon segments attached to their cell bodies survive to the proximity of the lamina.In contrast, axon segments in the lamina and behind the eye degenerate.These experiments provide strong evidence for a local insult to axons in the optic nerve.

View Article: PubMed Central - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.

ABSTRACT
Here, we use a mouse model (DBA/2J) to readdress the location of insult(s) to retinal ganglion cells (RGCs) in glaucoma. We localize an early sign of axon damage to an astrocyte-rich region of the optic nerve just posterior to the retina, analogous to the lamina cribrosa. In this region, a network of astrocytes associates intimately with RGC axons. Using BAX-deficient DBA/2J mice, which retain all of their RGCs, we provide experimental evidence for an insult within or very close to the lamina in the optic nerve. We show that proximal axon segments attached to their cell bodies survive to the proximity of the lamina. In contrast, axon segments in the lamina and behind the eye degenerate. Finally, the Wld(s) allele, which is known to protect against insults to axons, strongly protects against DBA/2J glaucoma and preserves RGC activity as measured by pattern electroretinography. These experiments provide strong evidence for a local insult to axons in the optic nerve.

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Axon degeneration is regionalized in the lamina and corresponds to fan-shaped RGC loss in the retina. (A–F) Compressed Z stack images through the lamina of DBA/2J nerves with increasing levels of glaucomatous damage (neurofilaments, green; GFAP positive glia, red). Axon loss/survival is clearly regionalized to different areas of the optic nerve and not randomly distributed. (G and H) The retina and corresponding lamina region of an eye with moderate glaucoma. Discrete fan-shaped areas of RGC loss are apparent in the retina (dotted “V,” G) and appear to correspond to two regionalized areas of axon loss in the lamina (dotted boxes, H). This is consistent with localized damage to axons within the lamina leading to fan-shaped patterns of RGC loss in the retina but it was not possible to follow the region of axon loss unambiguously through the whole optic nerve head. Bars, 50 μm.
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fig6: Axon degeneration is regionalized in the lamina and corresponds to fan-shaped RGC loss in the retina. (A–F) Compressed Z stack images through the lamina of DBA/2J nerves with increasing levels of glaucomatous damage (neurofilaments, green; GFAP positive glia, red). Axon loss/survival is clearly regionalized to different areas of the optic nerve and not randomly distributed. (G and H) The retina and corresponding lamina region of an eye with moderate glaucoma. Discrete fan-shaped areas of RGC loss are apparent in the retina (dotted “V,” G) and appear to correspond to two regionalized areas of axon loss in the lamina (dotted boxes, H). This is consistent with localized damage to axons within the lamina leading to fan-shaped patterns of RGC loss in the retina but it was not possible to follow the region of axon loss unambiguously through the whole optic nerve head. Bars, 50 μm.

Mentions: We, and others, have shown that RGC loss in the retinas of DBA/2 mice occurs regionally (Danias et al., 2003; Jakobs et al., 2005; Schlamp et al., 2006). Consistent with this, axon loss was not uniform in the lamina but occurred in discrete regions that varied from nerve to nerve (Fig. 6, A–F).


Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma.

Howell GR, Libby RT, Jakobs TC, Smith RS, Phalan FC, Barter JW, Barbay JM, Marchant JK, Mahesh N, Porciatti V, Whitmore AV, Masland RH, John SW - J. Cell Biol. (2007)

Axon degeneration is regionalized in the lamina and corresponds to fan-shaped RGC loss in the retina. (A–F) Compressed Z stack images through the lamina of DBA/2J nerves with increasing levels of glaucomatous damage (neurofilaments, green; GFAP positive glia, red). Axon loss/survival is clearly regionalized to different areas of the optic nerve and not randomly distributed. (G and H) The retina and corresponding lamina region of an eye with moderate glaucoma. Discrete fan-shaped areas of RGC loss are apparent in the retina (dotted “V,” G) and appear to correspond to two regionalized areas of axon loss in the lamina (dotted boxes, H). This is consistent with localized damage to axons within the lamina leading to fan-shaped patterns of RGC loss in the retina but it was not possible to follow the region of axon loss unambiguously through the whole optic nerve head. Bars, 50 μm.
© Copyright Policy
Related In: Results  -  Collection

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fig6: Axon degeneration is regionalized in the lamina and corresponds to fan-shaped RGC loss in the retina. (A–F) Compressed Z stack images through the lamina of DBA/2J nerves with increasing levels of glaucomatous damage (neurofilaments, green; GFAP positive glia, red). Axon loss/survival is clearly regionalized to different areas of the optic nerve and not randomly distributed. (G and H) The retina and corresponding lamina region of an eye with moderate glaucoma. Discrete fan-shaped areas of RGC loss are apparent in the retina (dotted “V,” G) and appear to correspond to two regionalized areas of axon loss in the lamina (dotted boxes, H). This is consistent with localized damage to axons within the lamina leading to fan-shaped patterns of RGC loss in the retina but it was not possible to follow the region of axon loss unambiguously through the whole optic nerve head. Bars, 50 μm.
Mentions: We, and others, have shown that RGC loss in the retinas of DBA/2 mice occurs regionally (Danias et al., 2003; Jakobs et al., 2005; Schlamp et al., 2006). Consistent with this, axon loss was not uniform in the lamina but occurred in discrete regions that varied from nerve to nerve (Fig. 6, A–F).

Bottom Line: We show that proximal axon segments attached to their cell bodies survive to the proximity of the lamina.In contrast, axon segments in the lamina and behind the eye degenerate.These experiments provide strong evidence for a local insult to axons in the optic nerve.

View Article: PubMed Central - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.

ABSTRACT
Here, we use a mouse model (DBA/2J) to readdress the location of insult(s) to retinal ganglion cells (RGCs) in glaucoma. We localize an early sign of axon damage to an astrocyte-rich region of the optic nerve just posterior to the retina, analogous to the lamina cribrosa. In this region, a network of astrocytes associates intimately with RGC axons. Using BAX-deficient DBA/2J mice, which retain all of their RGCs, we provide experimental evidence for an insult within or very close to the lamina in the optic nerve. We show that proximal axon segments attached to their cell bodies survive to the proximity of the lamina. In contrast, axon segments in the lamina and behind the eye degenerate. Finally, the Wld(s) allele, which is known to protect against insults to axons, strongly protects against DBA/2J glaucoma and preserves RGC activity as measured by pattern electroretinography. These experiments provide strong evidence for a local insult to axons in the optic nerve.

Show MeSH
Related in: MedlinePlus