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Published online December 24, 2007
doi:10.1083/jcb.200706181
The Journal of Cell Biology, Vol. 179, No. 7, 1523-1537
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Howell et al.
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Article

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

Gareth R. Howell1, Richard T. Libby1, Tatjana C. Jakobs2, Richard S. Smith1,3, F. Campbell Phalan1,3, Joseph W. Barter1,3, Jessica M. Barbay1, Jeffrey K. Marchant4, Nagaraju Mahesh5, Vittorio Porciatti5, Alan V. Whitmore1, Richard H. Masland2, and Simon W. M. John1,3,6

1 The Jackson Laboratory, Bar Harbor, ME 04609
2 Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
3 The Howard Hughes Medical Institute, Bar Harbor, ME 04609
4 Department of Anatomy and Cell Biology, Tufts University of Medicine, Boston, MA 02111
5 Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL 33136
6 Department of Ophthalmology, Tufts University of Medicine, Boston, MA 02111

Correspondence to Simon W.M. John: simon.john{at}jax.org

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 Wlds 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.

G.R. Howell and R.T. Libby contributed equally to this work.

R.T. Libby's present address is University of Rochester Eye Institute, University of Rochester Medical Center, Rochester, NY.

Abbreviations used in this paper: ECM, extracellular matrix; GFAP, glial fibrillary acidic protein; H&E, hematoxylin and eosin; PERG, pattern electroretinography; PPD, paraphenylenediamine; RGC, retinal ganglion cell.


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