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, SoRa R. Lee, Nathan J. Coorey, Murray Killingsworth, Lawrence (Larry) Sherman, Mark C. Gillies

    Research output: Contribution to journalArticle

    110 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 (US)
    Pages (from-to)15715-15727
    Number of pages13
    JournalJournal of Neuroscience
    Volume32
    Issue number45
    DOIs
    StatePublished - Nov 7 2012

    Fingerprint

    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

    ASJC Scopus subject areas

    • Neuroscience(all)

    Cite this

    Shen, W., Fruttiger, M., Zhu, L., Chung, S. H., Barnett, N. L., Kirk, J. K., ... Gillies, M. C. (2012). Conditional müller cell ablation causes independent neuronal and vascular pathologies in a novel transgenic model. Journal of Neuroscience, 32(45), 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, SoRa R.; Coorey, Nathan J.; Killingsworth, Murray; Sherman, Lawrence (Larry); Gillies, Mark C.

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

    Research output: Contribution to journalArticle

    Shen, W, Fruttiger, M, Zhu, L, Chung, SH, Barnett, NL, Kirk, JK, Lee, SR, Coorey, NJ, Killingsworth, M, Sherman, LL & 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
    Shen, Weiyong ; Fruttiger, Marcus ; Zhu, Ling ; Chung, Sook H. ; Barnett, Nigel L. ; Kirk, Joshua K. ; Lee, SoRa R. ; Coorey, Nathan J. ; Killingsworth, Murray ; Sherman, Lawrence (Larry) ; 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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