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An Introduction to Retinal Remodeling in Inherited and Acquired Retinal Degenerations
(modified from Marc, Jones, Watt and Strettoi 2003 Progress in Retinal and Eye Research PDF)
    Mammalian retinal degenerations initiated by gene defects in rods, cones or the retinal pigmented epithelium (RPE) often trigger loss of the sensory retina, effectively leaving the neural retina deafferented. The neural retina responds to this challenge by remodeling, first by subtle changes in neuronal structure and later by large-scale reorganization. Retinal degenerations in the mammalian retina generally progress through three phases. Phase 1 initiates with expression of a primary insult, followed by phase 2 photoreceptor death that ablates the sensory retina via initial photoreceptor stress, phenotype deconstruction, irreversible stress and cell death, including bystander effects or loss of trophic support. The loss of cones heralds phase 3: a protracted period of global remodeling of the remnant neural retina. Remodeling resembles the responses of many CNS assemblies to deafferentation or trauma, and includes neuronal cell death, neuronal and glial migration, elaboration of new neurites and synapses, rewiring of retinal circuits, glial hypertrophy and the evolution of a fibrotic glial seal that isolates the remnant neural retina from the surviving RPE and choroid.

    New data indicate that remodeling in degenerative retinal diseases may be even more severe than initially believed: in the LD rat model, as well as human AMD, both glia and neurons break through into the choroid and emigrate from the retina, further depleting the remnant retina of functioning neurons (Jones et al., 2003, ARVO abs 5124; Sullivan et al., 2003, IOVS 44:856-865).

    Retinal remodeling is not plasticity, but represents the invocation of mechanisms resembling developmental and CNS plasticities. Together, neuronal remodeling and the formation of the glial seal may abrogate many cellular and bionic rescue strategies. However, survivor neurons appear to be stable, healthy, active cells and given the evidence of their reactivity to deafferentation, it may be possible to influence their emergent rewiring and migration habits.

Marclab remodeling publications
Marc RE, BW Jones, CB Watt, F Vazquez-Chona, D. Vaughan, D. Organisciak 2008 Extreme Retinal Remodeling Triggered by Light Damage: Implications for AMD. In review: Molecular Vision.
Marc RE, BW Jones, JR Anderson, K Kinard, DW Marshak, JH Wilson, TG Wensel, RJ Lucas 2007 Neural reprogramming in retinal degenerations. Invest Ophthalmol Vis Sci 48: 3364-3371. PubMed PDF
Marc RE. 2007 Functional Neuroanatomy of the Retina in Albert and Jakobiec's Principles and Practice of Ophthalmology, 3rd edition (Eds Albert and Miller) Elsevier, in press PDF
Jones BW, RE Marc, CB Watt, DK Vaughan, DT Organisciak 2006 Chapter: Neural plasticity revealed by light-induced photoreceptor lesions. Retinal Degenerative Diseases, Springer, (New York), pp. 405-410.
Jones BW, CB Watt and RE Marc. 2005 Review: Retinal remodeling in retinal degenerations. Clinical and Experimental Optometry 88: 282-291. PubMed PDF
Jones BW and RE Marc. 2005 Review: Retinal remodeling during retinal degeneration. Experimental Eye Research, 81: 121-244. PubMed PDF
Marc RE, BW Jones and CB Watt. 2005 Review: Retinal remodeling: Circuitry revisions triggered by photoreceptor degeneration. In Plasticity in the Visual system: from Genes to Circuits. Eds, Pinaud et al., Springer, pp. 33-54.
Sarthy VP, L Pignataro, T Pannicke, M Weick, A Reichenbach, T Harada, K Tanaka and RE Marc 2005 Glutamate Transport by Retinal Müller Cells in Glutamate /Aspartate Transporter -knockout mice. Glia 49:184-196 PubMed PDF
Rohrer B, R Blanco, RE Marc, MB Lloyd, D Bok, DM Schneeweis, LF Reichardt 2004 Functionally intact glutamate-mediated signaling in bipolar-cells of the Trkb knockout mouse retina. Visual Neurosci 21:703-13. PubMed PDF
Marc RE, BW Jones, CB Watt and E Strettoi 2003 Review: Neural Remodeling in Retinal Degeneration. Progress in Retinal and Eye Research 22: 607-655. PubMed PDF
Marc RE, BW Jones 2003 Retinal remodeling in inherited photoreceptor degenerations. Molecular Neurobiology 28: 139-148. PubMed PDF
Jones BW, CB Watt, JM Frederick, W Baehr, CK Chen, EM Levine, AH Milam, MM LaVail, RE Marc 2003 Retinal remodeling triggered by photoreceptor degenerations. J Comp Neurol 464: 1-16. PubMed PDF
Marc RE 2002 Review: A review of: Retinal Cell Rescue - The Sixth Annual Vision Research Conference. Investigational Drugs: Weekly Highlights June 2002: 53-60. PDF
A Table of Natural and Experimental Remodeling Systems updated 13 May 2003
The following datasets summarize our analyses to date of retinal remodeling attributes in a number of natural and experimental models of photoreceptor/RPE degeneration using the strategy of computational molecular phenotyping (Marc and Jones 2002, J Neurosci. 22: 413-427).

A Request for material:We are continually expanding and refining this collection. Prospective collaborators should contact:

source gene model type n onset neuron
strict neuron
inv of
A mixed human RP natural 20 ? x x x x x x x x x x ?
B rho rat S344ter transgenic 9 340 x x x x x x x x x x ?
B rho rat P23H transgenic 12 372 x x x x x x x x x x ?
B mertk rat RCS natural 7 270 x x x x x x x x x x ?
C ------- rat LD induced 90 120 x x x x x x x x o o x
B pde6b mouse rd1 natural 9 610 x x x x x x x x x x ?
D pde6b/LCR mouse rdcl transgenic 20 340 x x x x x x x x o o ?
E RGS9 mouse TG9N transgenic 19 160 x x x x x x x x x x ?
F rho mouse GHL transgenic 12 555 x x x x x x x x x x ?
F rho mouse rho-/- knockout 4 365 o o o o x o o x o o o
E rho mouse rhoDCTA transgenic 8 541 o o o o x o o x o o o
B ? mouse nr natural 3 300 x x x x x x x x o x ?
B agtpbp1 mouse pcd natural 2 321 o o o o o o x x o o o
B prph2 mouse rd2 natural 1 >541 o o o o o o o x o o o
G elovl4 mouse elovl4-/- knockout 3 >180 o o o o o o o x x o o
H chx10 mouse orJ natural 3 <0 x x * x x x x o x x ?
H p27Kip1 mouse p27Kip1orj knockout 1 <63 x x x x x x x o o o ?

x present, o absent, ? undetermined, n number of samples, onset earliest observed remodeling onset in post-natal days, neuron death non-photoreceptor cell death in the neuronal retina, strict constrictions of the inner plexiform layer, neuron migxn neuronal migration into the distal and proximal retina; neuron fasc ectopic fascicles of neurites, microneuroma ectopic neuropil foci, glial migxn glial migration, glial cols hypertrophic glial columns, glial seals fibrotic glial processes at the distal margin of the retina, vasc inv invasion of choroidal vessels, rpe inv RPE invasion, inv of choroid emigration of glia and neurons into choroid.** Only isolated retinal patches survive in chx10. **The p27 Kip1 knockout rescues hypocellularity in chx10 but also exhibits neuronal remodeling.

Collaborative Sources
A  Ann H. Milam, Univ Pennsylvania & Foundation Fighting Blindness
B  Matthew M. LaVail, Univ California San Francisco
C  Daniel.T. Organisciak, Wright State University & Dana K Vaughn, Univ Wisconsin, Oshkosh
D  Robert J. Lucas, Imperial College, London
E  Ching-Kang Jason Chen, Univ Utah
F  Wolfgang Baehr, Jeanne M. Frederick, Univ Utah
G  Kang Zhang, Univ Utah
H  Edward M. Levine, Univ Utah

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