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Rgcs1, a dominant QTL that affects retinal ganglion cell death after optic nerve crush in mice
Joel A Dietz, Yan Li, Lisa M Chung, Brian S Yandell, Cassandra L Schlamp, Robert W Nickells
BMC Neuroscience , 2008, DOI: 10.1186/1471-2202-9-74
Abstract: Genome wide mapping of the F2 mice using microsatellite markers, detected a single highly significant quantitative trait locus in a 25 cM (58 Mb) interval on chromosome 5 (Chr5.loc34-59 cM). No interacting loci were detected at the resolution of this screen. We have designated this locus as Retinal ganglion cell susceptible 1, Rgcs1. In silico analysis of this region revealed the presence of 578 genes or expressed sequence tags, 4 of which are highly expressed in the ganglion cell layer of the mammalian retina, and 2 of which are suspected susceptibility alleles in chronic neurodegenerative diseases. In addition, 25 genes contain 36 known single nucleotide polymorphisms that create nonsynonymous amino acid changes between the two parental strains. Collectively, this analysis has identified 7 potential candidate genes that may affect ganglion cell death.The process of ganglion cell death is likely one of the many facets of glaucoma susceptibility. A novel dominant locus has been identified that affects sensitivity of ganglion cells to optic nerve crush. The allele responsible for this sensitivity may also be a susceptibility allele for glaucoma.Glaucoma is a blinding disease characterized by the progressive death of retinal ganglion cells. The principal risk factor for glaucoma is elevated intraocular pressure (IOP) [1-3]. Biomechanical engineering studies suggest that IOP-related stress is focused on ganglion cell axons exiting the eye through the lamina cribrosa [4,5]. Current models suggest that optic nerve glia are adversely affected and that this leads first to destruction of the ganglion cell axon, and secondarily, to the apoptotic death of the ganglion cell soma (reviewed by [6,7]).Glaucoma is a complex genetic disease [8]. After elevated IOP, family history is the next most important risk factor [9,10]. While many important studies have revealed a great deal about the genetics of this disease, the majority of these have been restricted to relatively rare form
Dominant inheritance of retinal ganglion cell resistance to optic nerve crush in mice
Yan Li, Sheila J Semaan, Cassandra L Schlamp, Robert W Nickells
BMC Neuroscience , 2007, DOI: 10.1186/1471-2202-8-19
Abstract: Inbred lines showed varying levels of susceptibility to optic nerve crush. DBA/2J mice were most resistant and BALB/cByJ mice were most susceptible. F1 mice from these lines inherited the DBA/2J phenotype, while N2 backcross mice exhibited the BALB/cByJ phenotype. F2 mice exhibited an intermediate phenotype. A Wright Formula calculation suggested as few as 2 dominant loci were linked to the resistance phenotype, which was corroborated by a Punnett Square analysis of the distribution of the mean phenotype in each cross. The levels of latent Bax mRNA were the same in both lines, and Bax alleles did not segregate with phenotype in N2 and F2 mice.Inbred mice show different levels of resistance to optic nerve crush. The resistance phenotype is heritable in a dominant fashion involving relatively few loci. Bax was excluded as a candidate gene for this phenotype.The influence of complex genetics on neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, and Multiple Sclerosis, is evidenced by the consideration that family history is a significant risk factor for candidate patients [1-3]. Although interacting loci may influence a variety of different factors, one common element is the process of neuronal cell death, which predominantly occurs by apoptosis [4,5]. Consequently, consideration of the genes that affect susceptibility to disease should include those that affect both the response(s) of neurons to damaging stimuli and the process of cell death itself. Several studies, using screening strategies of inbred mouse lines, have reinforced the concept that genetic background has an influence on the level of susceptibility to neuronal damage [6-9]. At least 3 loci have been mapped, for example, that affect neuronal susceptibility to the Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [10,11].Primary open angle glaucoma is also a multifactorial neurodegenerative disease with a strong familial component [12-14]. This disease a
Protection by an Oral Disubstituted Hydroxylamine Derivative against Loss of Retinal Ganglion Cell Differentiation following Optic Nerve Crush  [PDF]
James D. Lindsey, Karen X. Duong-Polk, Yi Dai, Duy H. Nguyen, Christopher K. Leung, Robert N. Weinreb
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065966
Abstract: Thy-1 is a cell surface protein that is expressed during the differentiation of retinal ganglion cells (RGCs). Optic nerve injury induces progressive loss in the number of RGCs expressing Thy-1. The rate of this loss is fastest during the first week after optic nerve injury and slower in subsequent weeks. This study was undertaken to determine whether oral treatment with a water-soluble N-hydroxy-2,2,6,6-tetramethylpiperidine derivative (OT-440) protects against loss of Thy-1 promoter activation following optic nerve crush and whether this effect targets the earlier quick phase or the later slow phase. The retina of mice expressing cyan fluorescent protein under control of the Thy-1 promoter (Thy1-CFP mice) was imaged using a blue-light confocal scanning laser ophthalmoscope (bCSLO). These mice then received oral OT-440 prepared in cream cheese or dissolved in water, or plain vehicle, for two weeks and were imaged again prior to unilateral optic nerve crush. Treatments and weekly imaging continued for four more weeks. Fluorescent neurons were counted in the same defined retinal areas imaged at each time point in a masked fashion. When the counts at each time point were directly compared, the numbers of fluorescent cells at each time point were greater in the animals that received OT-440 in cream cheese by 8%, 27%, 52% and 60% than in corresponding control animals at 1, 2, 3 and 4 weeks after optic nerve crush. Similar results were obtained when the vehicle was water. Rate analysis indicated the protective effect of OT-440 was greatest during the first two weeks and was maintained in the second two weeks after crush for both the cream cheese vehicle study and water vehicle study. Because most of the fluorescent cells detected by bCSLO are RGCs, these findings suggest that oral OT-440 can either protect against or delay early degenerative responses occurring in RGCs following optic nerve injury.
Hydrogen-Rich Saline Promotes Survival of Retinal Ganglion Cells in a Rat Model of Optic Nerve Crush  [PDF]
Jing-chuan Sun, Tao Xu, Qiao Zuo, Ruo-bing Wang, Ai-qing Qi, Wen-luo Cao, Ai-jun Sun, Xue-jun Sun, Jiajun Xu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099299
Abstract: Objective To investigate the effect of molecular hydrogen (H2) in a rat model subjected to optic nerve crush (ONC). Methods We tested the hypothesis that after optic nerve crush (ONC), retinal ganglion cell (RGC) could be protected by H2. Rats in different groups received saline or hydrogen-rich saline every day for 14 days after ONC. Retinas from animals in each group underwent measurements of hematoxylin and eosin (H&E) staining, cholera toxin beta (CTB) tracing, gamma synuclein staining, and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining 2 weeks post operation. Flash visual evoked potentials (FVEP) and pupillary light reflex (PLR) were then tested to evaluate the function of optic nerve. The malondialdehyde (MDA) level in retina was evaluated. Results H&E, gamma synuclein staining and CTB tracing showed that the survival rate of RGCs in hydrogen saline-treated group was significantly higher than that in saline-treated group. Apoptosis of RGCs assessed by TUNEL staining were less observed in hydrogen saline-treated group. The MDA level in retina of H2 group was much lower than that in placebo group. Furthermore, animals treated with hydrogen saline showed better function of optic nerve in assessments of FVEP and PLR. Conclusion These results demonstrated that H2 protects RGCs and helps preserve the visual function after ONC and had a neuroprotective effect in a rat model subjected to ONC.
Neurogenesis of Retinal Ganglion Cells Is Not Essential to Visual Functional Recovery after Optic Nerve Injury in Adult Zebrafish  [PDF]
Suqi Zou, Chen Tian, Shuchao Ge, Bing Hu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057280
Abstract: Zebrafish central nervous system (CNS) possesses a strong neural regeneration ability to restore visual function completely after optic nerve injury (ONI). However, whether neurogenesis of retinal ganglion cell (RGC) contributes to functional recovery remains controversial. Our quantitative analysis of RGCs in different ONI models showed that almost all RGCs survived in optic nerve crush (ONC) model; while over 90% of RGCs survived in the first 2 weeks with 75% remaining after 7 weeks in optic nerve transection (ONT) model. Retrograde labeling from tectum revealed a surprising regeneration rate, with over 90% and over 50% of RGCs regrowing axons to tectum at the first week in ONC and ONT model respectively. In the latter one, the number of regenerative RGCs after 4 weeks had no significant difference from the control group. As for neurogenesis, newborn RGCs were rarely detected either by double retrograde labeling or BrdU marker. Since few RGCs died, microglia number showed a temporary increase at 3 days post injury (dpi) and a decrease at 14 dpi. Finally, myelin structure within retina kept integrity and optomotor response (OMR) test demonstrated visual functional restoration at 5 weeks post injury (wpi). In conclusion, our results have directly shown that RGC survival and axon regrowth are responsible for functional recovery after ONI in adult zebrafish.
AMIGO3 Is an NgR1/p75 Co-Receptor Signalling Axon Growth Inhibition in the Acute Phase of Adult Central Nervous System Injury  [PDF]
Zubair Ahmed, Michael R. Douglas, Gabrielle John, Martin Berry, Ann Logan
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061878
Abstract: Axon regeneration in the injured adult CNS is reportedly inhibited by myelin-derived inhibitory molecules, after binding to a receptor complex comprised of the Nogo-66 receptor (NgR1) and two transmembrane co-receptors p75/TROY and LINGO-1. However, the post-injury expression pattern for LINGO-1 is inconsistent with its proposed function. We demonstrated that AMIGO3 levels were significantly higher acutely than those of LINGO-1 in dorsal column lesions and reduced in models of dorsal root ganglion neuron (DRGN) axon regeneration. Similarly, AMIGO3 levels were raised in the retina immediately after optic nerve crush, whilst levels were suppressed in regenerating optic nerves, induced by intravitreal peripheral nerve implantation. AMIGO3 interacted functionally with NgR1-p75/TROY in non-neuronal cells and in brain lysates, mediating RhoA activation in response to CNS myelin. Knockdown of AMIGO3 in myelin-inhibited adult primary DRG and retinal cultures promoted disinhibited neurite growth when cells were stimulated with appropriate neurotrophic factors. These findings demonstrate that AMIGO3 substitutes for LINGO-1 in the NgR1-p75/TROY inhibitory signalling complex and suggests that the NgR1-p75/TROY-AMIGO3 receptor complex mediates myelin-induced inhibition of axon growth acutely in the CNS. Thus, antagonizing AMIGO3 rather than LINGO-1 immediately after CNS injury is likely to be a more effective therapeutic strategy for promoting CNS axon regeneration when combined with neurotrophic factor administration.
Differential response of C57BL/6J mouse and DBA/2J mouse to optic nerve crush
Templeton Justin P,Nassr Mohamed,Vazquez-Chona Felix,Freeman-Anderson Natalie E
BMC Neuroscience , 2009, DOI: 10.1186/1471-2202-10-90
Abstract: Background Retinal ganglion cell (RGC) death is the final consequence of many blinding diseases, where there is considerable variation in the time course and severity of RGC loss. Indeed, this process appears to be influenced by a wide variety of genetic and environmental factors. In this study we explored the genetic basis for differences in ganglion cell death in two inbred strains of mice. Results We found that RGCs are more susceptible to death following optic nerve crush in C57BL/6J mice (54% survival) than in DBA/2J mice (62% survival). Using the Illumina Mouse-6 microarray, we identified 1,580 genes with significant change in expression following optic nerve crush in these two strains of mice. Our analysis of the changes occurring after optic nerve crush demonstrated that the greatest amount of change (44% of the variance) was due to the injury itself. This included changes associated with ganglion cell death, reactive gliosis, and abortive regeneration. The second pattern of gene changes (23% of the variance) was primarily related to differences in gene expressions observed between the C57BL/6J and DBA/2J mouse strains. The remaining changes in gene expression represent interactions between the effects of optic nerve crush and the genetic background of the mouse. We extracted one genetic network from this dataset that appears to be related to tissue remodeling. One of the most intriguing sets of changes included members of the crystallin family of genes, which may represent a signature of pathways modulating the susceptibility of cells to death. Conclusion Differential responses to optic nerve crush between two widely used strains of mice were used to define molecular networks associated with ganglion cell death and reactive gliosis. These results form the basis for our continuing interest in the modifiers of retinal injury.
Rac1 Selective Activation Improves Retina Ganglion Cell Survival and Regeneration  [PDF]
Erika Lorenzetto, Michele Ettorre, Valeria Pontelli, Matteo Bolomini-Vittori, Silvia Bolognin, Simone Zorzan, Carlo Laudanna, Mario Buffelli
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064350
Abstract: In adult mammals, after optic nerve injury, retinal ganglion cells (RGCs) do not regenerate their axons and most of them die by apoptosis within a few days. Recently, several strategies that activate neuronal intracellular pathways were proposed to prevent such degenerative processes. The rho-related small GTPase Rac1 is part of a complex, still not fully understood, intracellular signaling network, mediating in neurons many effects, including axon growth and cell survival. However, its role in neuronal survival and regeneration in vivo has not yet been properly investigated. To address this point we intravitreally injected selective cell-penetrating Rac1 mutants after optic nerve crush and studied the effect on RGC survival and axonal regeneration. We injected two well-characterized L61 constitutively active Tat-Rac1 fusion protein mutants, in which a second F37A or Y40C mutation confers selectivity in downstream signaling pathways. Results showed that, 15 days after crush, both mutants were able to improve survival and to prevent dendrite degeneration, while the one harboring the F37A mutation also improved axonal regeneration. The treatment with F37A mutant for one month did not improve the axonal elongation respect to 15 days. Furthermore, we found an increase of Pak1 T212 phosphorylation and ERK1/2 expression in RGCs after F37A treatment, whereas ERK1/2 was more activated in glial cells after Y40C administration. Our data suggest that the selective activation of distinct Rac1-dependent pathways could represent a therapeutic strategy to counteract neuronal degenerative processes in the retina.
Perturbations of MicroRNA Function in Mouse Dicer Mutants Produce Retinal Defects and Lead to Aberrant Axon Pathfinding at the Optic Chiasm  [PDF]
Rita Pinter,Robert Hindges
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010021
Abstract: During development axons encounter a variety of choice points where they have to make appropriate pathfinding decisions. The optic chiasm is a major decision point for retinal ganglion cell (RGC) axons en route to their target in order to ensure the correct wiring of the visual system. MicroRNAs (miRNAs) belong to the class of small non-coding RNA molecules and have been identified as important regulators of a variety of processes during embryonic development. However, their involvement in axon guidance decisions is less clear.
The progressive nature of Wallerian degeneration in wild-type and slow Wallerian degeneration (WldS) nerves
Bogdan Beirowski, Robert Adalbert, Diana Wagner, Daniela S Grumme, Klaus Addicks, Richard R Ribchester, Michael P Coleman
BMC Neuroscience , 2005, DOI: 10.1186/1471-2202-6-6
Abstract: In wild-type nerves, we directly observed partially fragmented axons (average 5.3%) among a majority of fully intact or degenerated axons 37–42 h after transection and 40–44 h after crush injury. Axons exist in this state only transiently, probably for less than one hour. Surprisingly, axons degenerated anterogradely after transection but retrogradely after a crush, but in both cases a sharp boundary separated intact and fragmented regions of individual axons, indicating that Wallerian degeneration progresses as a wave sequentially affecting adjacent regions of the axon. In contrast, most or all WldS axons were partially fragmented 15–25 days after nerve lesion, WldS axons degenerated anterogradely independent of lesion type, and signs of degeneration increased gradually along the nerve instead of abruptly. Furthermore, the first signs of degeneration were short constrictions, not complete breaks.We conclude that Wallerian degeneration progresses rapidly along individual wild-type axons after a heterogeneous latent phase. The speed of progression and its ability to travel in either direction challenges earlier models in which clearance of trophic or regulatory factors by axonal transport triggers degeneration. WldS axons, once they finally degenerate, do so by a fundamentally different mechanism, indicated by differences in the rate, direction and abruptness of progression, and by different early morphological signs of degeneration. These observations suggest that WldS axons undergo a slow anterograde decay as axonal components are gradually depleted, and do not simply follow the degeneration pathway of wild-type axons at a slower rate.Wallerian degeneration, the characteristic degeneration sequence of nerve fibres separated from their cell bodies, was described by Waller in 1850 [1,2]. Following various forms of axon injury this rapid degeneration process begins with degradation of axoplasm and axolemma accompanied by development of axonal and myelin debris that is
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