The BXD Mouse Strains are a Model System for Studying Optic Nerve Regeneration

AbstractThe present study is designed to identify the influences of genetic background to optic nerve regeneration using the two parental strains C57BL/6J and DBA/2J and 7 BXD recombinant inbred strains. To study regeneration in the optic nerve, Pten was knocked down in the retinal ganglion cells using AAV, and a mild inflammatory response was induced by an intravitreal injection of zymosan with CPT-cAMP, and the axons were damaged by optic nerve crush (ONC). Regenerating axons were labeled by Cholera Toxin B and quantified 14 days after ONC. The number of axons at 0.5 mm and 1 mm from the crush site were counted. In addition, we measured the distance that 5 axons had grown down the nerve and the longest distance a single axon reached. Results showed a considerable amount of differential axonal growth across all 9 BXD strains. There was a significant difference (P=0.014 Mann-Whitney U test) in the regenerative capacity in the number of axons reaching 0.5 mm from a low of 1487.6 ± 264.9 axons in BXD102 to a high of 4175.8 ± 648.6 axons in BXD29. There were also significant differences (P=0.014 Mann-Whitney U test) in the distance axons traveled, looking at a minimum of 5 axons with the shortest distance was 787.2 ± 46.5µm in BXD102 to a maximum distance of 2025.5 ± 223.3µm in BXD29. These results reveal that genetic background can modulate axonal regeneration and that the BXD strains are a particularly well-suited model system.

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A second episode of ganglion cell death takes place when an optic nerve regenerates for a second time in the frog

Visual Neuroscience ◽

10.1017/s0952523800003692 ◽

1993 ◽

Vol 10 (2) ◽

pp. 297-301 ◽

Cited By ~ 7

Author(s):

L. D. Beazley ◽

J.E. Darby

Keyword(s):

Cell Death ◽

Optic Nerve ◽

Ganglion Cell ◽

Ganglion Cells ◽

Cresyl Violet ◽

Retinal Ganglion ◽

Nerve Crush ◽

Optic Nerve Regeneration ◽

Ability To Regenerate ◽

Ganglion Cell Death

AbstractWe have previously reported that during optic nerve regeneration in the frog, 30–40% of retinal ganglion cells die, the loss being complete within 10 weeks. In the present study, we crushed the optic nerve, waited 10 weeks, and then recrushed the nerve at the same site. Retinae were examined 10 weeks later. We estimated ganglion cell numbers from cresyl-violet-stained wholemounts and found a fall of 53% compared to normals. The loss was significantly greater than the losses of 36% and 35%, respectively, in frogs which received a single optic nerve crush and were examined 10 or 20–24 weeks later. The results indicate that a second episode of ganglion cell death took place when the optic nerve regenerated a second time. We conclude that ganglion cells in the frog are not comprised of two subpopulations, only one of which intrinsically possesses the ability to regenerate.

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Prevention of optic nerve regeneration in the frogHyla moorei transiently delays the death of some ganglion cells

The Journal of Comparative Neurology ◽

10.1002/cne.902790203 ◽

1989 ◽

Vol 279 (2) ◽

pp. 187-198 ◽

Cited By ~ 11

Author(s):

M. F. Humphrey ◽

J. E. Darby ◽

L. D. Beazley

Keyword(s):

Optic Nerve ◽

Nerve Regeneration ◽

Ganglion Cells ◽

Optic Nerve Regeneration

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Loss of Rbfox1 Does Not Affect Survival of Retinal Ganglion Cells Injured by Optic Nerve Crush

Frontiers in Neuroscience ◽

10.3389/fnins.2021.687690 ◽

2021 ◽

Vol 15 ◽

Author(s):

Lei Gu ◽

Jacky M. Kwong ◽

Joseph Caprioli ◽

Natik Piri

Keyword(s):

Optic Nerve ◽

Retinal Ganglion Cells ◽

Gene Networks ◽

Rna Binding ◽

Ganglion Cells ◽

Statistical Significance ◽

Optic Nerve Crush ◽

Retinal Ganglion ◽

Nerve Crush ◽

Significant Difference

Rbfox1 is a multifunctional RNA binding protein that regulates alternative splicing, transcription, mRNA stability and translation. Its roles in neurogenesis and neuronal functions are well established. Recent studies also implicate Rbfox1 in the regulation of gene networks that support cell survival during stress. We have earlier characterized the expression of Rbfox1 in amacrine and retinal ganglion cells (RGCs) and showed that deletion of Rbfox1 in adult animals results in depth perception deficiency. The current study investigates the effect of Rbfox1 downregulation on survival of RGCs injured by optic nerve crush (ONC). Seven days after ONC, animals sustained severe degeneration of RGC axons in the optic nerve and significant loss of RGC somas. Semi-quantitative grading of optic nerve damage in control + ONC, control + tamoxifen + ONC, and Rbfox1–/– + ONC groups ranged from 4.6 to 4.8 on a scale of 1 (normal; no degenerated axons were noted) to 5 (total degeneration; all axons showed degenerated organelles, axonal content, and myelin sheath), indicating a severe degeneration. Among these three ONC groups, no statistical significance was observed when any two groups were compared. The number of RGC somas were quantitatively analyzed in superior, inferior, nasal and temporal retinal quadrants at 0.5, 1, and 1.5 mm from the center of the optic disc. The average RGC densities (cells/mm2) were: control 6,438 ± 1,203; control + ONC 2,779 ± 573; control + tamoxifen 6,163 ± 861; control + tamoxifen + ONC 2,573 ± 555; Rbfox1–/– 6,437 ± 893; and Rbfox1–/– + ONC 2,537 ± 526. The RGC loss in control + ONC, control + tamoxifen + ONC and Rbfox1–/– + ONC was 57% (P = 1.44954E-42), 58% (P = 1.37543E-57) and 61% (P = 5.552E-59) compared to RGC numbers in the relevant uninjured groups, respectively. No statistically significant difference was observed between any two groups of uninjured animals or between any two ONC groups. Our data indicate that Rbfox1-mediated pathways have no effect on survival of RGCs injured by ONC.

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Further study of the outward displacement of retinal ganglion cells during optic nerve regeneration, with a note on the normal cells of dogiel in the adult frog

The Journal of Comparative Neurology ◽

10.1002/cne.903010108 ◽

1990 ◽

Vol 301 (1) ◽

pp. 80-92 ◽

Cited By ~ 3

Author(s):

Eric L. Singman ◽

Frank Scalia

Keyword(s):

Optic Nerve ◽

Nerve Regeneration ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Normal Cells ◽

Optic Nerve Regeneration ◽

Adult Frog

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Gene expression analysis of zebrafish retinal ganglion cells during optic nerve regeneration identifies KLF6a and KLF7a as important regulators of axon regeneration

Developmental Biology ◽

10.1016/j.ydbio.2007.09.019 ◽

2007 ◽

Vol 312 (2) ◽

pp. 596-612 ◽

Cited By ~ 109

Author(s):

Matthew B. Veldman ◽

Michael A. Bemben ◽

Robert C. Thompson ◽

Daniel Goldman

Keyword(s):

Gene Expression ◽

Optic Nerve ◽

Nerve Regeneration ◽

Retinal Ganglion Cells ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Axon Regeneration ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Optic Nerve Regeneration

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Chemokine CCL5 promotes robust optic nerve regeneration and mediates many of the effects of CNTF gene therapy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2017282118 ◽

2021 ◽

Vol 118 (9) ◽

pp. e2017282118 ◽

Cited By ~ 1

Author(s):

Lili Xie ◽

Yuqin Yin ◽

Larry Benowitz

Keyword(s):

Gene Therapy ◽

Optic Nerve ◽

Nerve Regeneration ◽

Viral Vectors ◽

Ganglion Cells ◽

Projection Neurons ◽

Retinal Ganglion ◽

Optic Nerve Regeneration ◽

Beneficial Effects ◽

Chemokine Ligand

Ciliary neurotrophic factor (CNTF) is a leading therapeutic candidate for several ocular diseases and induces optic nerve regeneration in animal models. Paradoxically, however, although CNTF gene therapy promotes extensive regeneration, recombinant CNTF (rCNTF) has little effect. Because intraocular viral vectors induce inflammation, and because CNTF is an immune modulator, we investigated whether CNTF gene therapy acts indirectly through other immune mediators. The beneficial effects of CNTF gene therapy remained unchanged after deleting CNTF receptor alpha (CNTFRα) in retinal ganglion cells (RGCs), the projection neurons of the retina, but were diminished by depleting neutrophils or by genetically suppressing monocyte infiltration. CNTF gene therapy increased expression of C-C motif chemokine ligand 5 (CCL5) in immune cells and retinal glia, and recombinant CCL5 induced extensive axon regeneration. Conversely, CRISPR-mediated knockdown of the cognate receptor (CCR5) in RGCs or treating wild-type mice with a CCR5 antagonist repressed the effects of CNTF gene therapy. Thus, CCL5 is a previously unrecognized, potent activator of optic nerve regeneration and mediates many of the effects of CNTF gene therapy.

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