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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) | |||||||||||||||||
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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. | |||||||||||||||||
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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).
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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
A Table of Natural and Experimental Remodeling Systems updated 13 May 2003
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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). |
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A Request for material:We are continually expanding and refining this collection. Prospective collaborators should contact: |
| source | gene | model | type | n | onset |
neuron death |
strict |
neuron migxn |
neuron fasc |
micro- neuroma |
glial migxn |
glial cols |
glial seal |
vasc inv |
rpe inv |
inv of choroid |
| 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 | ? |
| Abbreviations |
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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.
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| 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 |