Conditional müller cell ablation causes independent neuronal and vascular pathologies in a novel transgenic model

Weiyong Shen, Marcus Fruttiger, Ling Zhu, Sook H. Chung, Nigel L. Barnett, Joshua K. Kirk, So Ra Lee, Nathan J. Coorey, Murray Killingsworth, Larry S. Sherman, Mark C. Gillies

Research output: Contribution to journalArticleResearchpeer-review

104 Citations (Scopus)

Abstract

Müller cells are the major glia of the retina that serve numerous functions essential to retinal homeostasis, yet the contribution of Müller glial dysfunction to retinal diseases remains largely unknown. We have developed a transgenic model using a portion of the regulatory region of the retinaldehyde binding protein 1 gene for conditional Müller cell ablation and the consequences of primary Müller cell dysfunction have been studied in adult mice. We found that selective ablation of Müller cells led to photoreceptor apoptosis, vascular telangiectasis, blood-retinal barrier breakdown and, later, intraretinal neovascularization. These changes were accompanied by impaired retinal function and an imbalance between vascular endothelial growth factor-A (VEGF-A) and pigment epithelium-derived factor. Intravitreal injection of ciliary neurotrophic factor inhibited photoreceptor injury but had no effect on the vasculopathy. Conversely, inhibition of VEGF-A activity attenuated vascular leak but did not protect photoreceptors. Our findings show that Müller glial deficiency may be an important upstream cause of retinal neuronal and vascular pathologies in retinal diseases. Combined neuropro-tective and anti-angiogenic therapies may be required to treat Müller cell deficiency in retinal diseases and in other parts of the CNS associated with glial dysfunction.

Original languageEnglish
Pages (from-to)15715-15727
Number of pages13
JournalJournal of Neuroscience
Volume32
Issue number45
DOIs
Publication statusPublished - 7 Nov 2012
Externally publishedYes

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Blood Vessels
Neuroglia
Retinal Diseases
Pathology
Vascular Endothelial Growth Factor A
Blood-Retinal Barrier
Retinaldehyde
Ciliary Neurotrophic Factor
Retinal Vessels
Telangiectasis
Intravitreal Injections
Nucleic Acid Regulatory Sequences
Retina
Carrier Proteins
Homeostasis
Apoptosis
Wounds and Injuries
Genes
Therapeutics

Cite this

Shen, Weiyong ; Fruttiger, Marcus ; Zhu, Ling ; Chung, Sook H. ; Barnett, Nigel L. ; Kirk, Joshua K. ; Lee, So Ra ; Coorey, Nathan J. ; Killingsworth, Murray ; Sherman, Larry S. ; Gillies, Mark C. / Conditional müller cell ablation causes independent neuronal and vascular pathologies in a novel transgenic model. In: Journal of Neuroscience. 2012 ; Vol. 32, No. 45. pp. 15715-15727.
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abstract = "M{\"u}ller cells are the major glia of the retina that serve numerous functions essential to retinal homeostasis, yet the contribution of M{\"u}ller glial dysfunction to retinal diseases remains largely unknown. We have developed a transgenic model using a portion of the regulatory region of the retinaldehyde binding protein 1 gene for conditional M{\"u}ller cell ablation and the consequences of primary M{\"u}ller cell dysfunction have been studied in adult mice. We found that selective ablation of M{\"u}ller cells led to photoreceptor apoptosis, vascular telangiectasis, blood-retinal barrier breakdown and, later, intraretinal neovascularization. These changes were accompanied by impaired retinal function and an imbalance between vascular endothelial growth factor-A (VEGF-A) and pigment epithelium-derived factor. Intravitreal injection of ciliary neurotrophic factor inhibited photoreceptor injury but had no effect on the vasculopathy. Conversely, inhibition of VEGF-A activity attenuated vascular leak but did not protect photoreceptors. Our findings show that M{\"u}ller glial deficiency may be an important upstream cause of retinal neuronal and vascular pathologies in retinal diseases. Combined neuropro-tective and anti-angiogenic therapies may be required to treat M{\"u}ller cell deficiency in retinal diseases and in other parts of the CNS associated with glial dysfunction.",
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Shen, W, Fruttiger, M, Zhu, L, Chung, SH, Barnett, NL, Kirk, JK, Lee, SR, Coorey, NJ, Killingsworth, M, Sherman, LS & Gillies, MC 2012, 'Conditional müller cell ablation causes independent neuronal and vascular pathologies in a novel transgenic model' Journal of Neuroscience, vol. 32, no. 45, pp. 15715-15727. https://doi.org/10.1523/JNEUROSCI.2841-12.2012

Conditional müller cell ablation causes independent neuronal and vascular pathologies in a novel transgenic model. / Shen, Weiyong; Fruttiger, Marcus; Zhu, Ling; Chung, Sook H.; Barnett, Nigel L.; Kirk, Joshua K.; Lee, So Ra; Coorey, Nathan J.; Killingsworth, Murray; Sherman, Larry S.; Gillies, Mark C.

In: Journal of Neuroscience, Vol. 32, No. 45, 07.11.2012, p. 15715-15727.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Shen, Weiyong

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AU - Kirk, Joshua K.

AU - Lee, So Ra

AU - Coorey, Nathan J.

AU - Killingsworth, Murray

AU - Sherman, Larry S.

AU - Gillies, Mark C.

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JF - Journal of Neuroscience

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