May 2006
Volume 47, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2006
Role of Altered Regulation of the Creb–Dependent Genes C–fos and Bcl–2 Following Acute Optic Nerve Damage for Retinal Ganglion Cell Death
Author Affiliations & Notes
  • C.O. Knop
    Otto–von–Guericke–University, Magdeburg, Germany
    Ophthalmology,
  • C. Mawrin
    Otto–von–Guericke–University, Magdeburg, Germany
    Institute of Neuropathology,
  • S. Tuchen
    Otto–von–Guericke–University, Magdeburg, Germany
    Ophthalmology,
  • M. Springer
    Ophthalmology, Armed Forces Hospital, Ulm, Germany
  • W. Behrens–Baumann
    Otto–von–Guericke–University, Magdeburg, Germany
    Ophthalmology,
  • C. Vorwerk
    Otto–von–Guericke–University, Magdeburg, Germany
    Ophthalmology,
  • Footnotes
    Commercial Relationships  C.O. Knop, None; C. Mawrin, None; S. Tuchen, None; M. Springer, None; W. Behrens–Baumann, None; C. Vorwerk, None.
  • Footnotes
    Support  BMBF–NBL3
Investigative Ophthalmology & Visual Science May 2006, Vol.47, 729. doi:
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      C.O. Knop, C. Mawrin, S. Tuchen, M. Springer, W. Behrens–Baumann, C. Vorwerk; Role of Altered Regulation of the Creb–Dependent Genes C–fos and Bcl–2 Following Acute Optic Nerve Damage for Retinal Ganglion Cell Death . Invest. Ophthalmol. Vis. Sci. 2006;47(13):729.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : The primary feature of glaucomatous retinopathy is the death of retinal ganglion cells. Recent data indicate that deregulation of apoptotic signaling might be involved in this process. Neuronal survival is critical dependent on neurotrophic factors, which exert their function via activation of the Ras–Phosphatidylinositol–3–kinase (PI3K)–pathway. This pathway substantially controlles the gene expression of the anti–apoptotic Bcl–2 protein via phosphorylation of CREB. Another CREB–dependend gene involved in the regulation of apoptosis is the immediate early gene c–Fos, but the role of c–Fos in glaucomatous eyes is not well understood. In the present study, we analyzed time–dependent changes in the activation of the MAPK–CREB signaling pathway and subsequent regulation of c–Fos and Bcl–2 expression in an acute rat optic nerve damage model.

Methods: : RGC damage was induced by unilateral optic nerve crush or ischemia in male Wistar rats. Eyes were removed at days 1, 3, 7, or 14 after experiment. Retinal tissue was processed for RNA extraction for real–time measurement of Bcl–2 and c–Fos mRNA. Additional tissue was used for protein extraction and subjected to western blot analysis of pMAPK, pCREB and pAkt expression levels. Formalin–fixed paraffin embedded eyes were used for pMAPK, pAkt, pCREB, Bcl–2, and c–Fos immunostaining. Apoptosis in retinal ganglion cells was determined by TUNEL and fluoro–jade staining.

Results: : Compared to control eyes, optic nerve crush resulted in a significant increase of c–Fos and a significant decreased of Bcl–2 expression as detected by immunohistochemistry and real–time PCR. The lowest Bcl–2 levels were measured at day 7, while c–Fos expression reached highest levels at day 1 following optic nerve damage. These effects were mediated by increased activation of both pMAPK and pCREB expression, while pAkt expression was nearly completely downregulated at days 1, 3, and 7 following optic nerve damage. Apoptosis in retinal tissue was detected especially at day 1 and day 7.

Conclusions: : Our data indicate that optic nerve damage activates pMAPK–pCREB signaling, but with different effects on pro–apoptotic genes like c–Fos and anti–apoptotic genes like Bcl–2. This altered regulation might explain the apoptotic ganglion cell death seen in human glaucoma.

Keywords: apoptosis/cell death • cell survival • ganglion cells 
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