Abstract
BackgroundCiliary neurotrophic factor (CNTF), a member of the interleukin-6 cytokine family, has been implicated in the development, differentiation and survival of retinal neurons. The mechanisms of CNTF action as well as its cellular targets in the retina are poorly understood. It has been postulated that some of the biological effects of CNTF are mediated through its action via retinal glial cells; however, molecular changes in retinal glia induced by CNTF have not been elucidated. We have, therefore, examined gene expression dynamics of purified Müller (glial) cells exposed to CNTF in vivo.Methodology/Principal FindingsMüller cells were flow-sorted from mgfap-egfp transgenic mice one or three days after intravitreal injection of CNTF. Microarray analysis using RNA from purified Müller cells showed differential expression of almost 1,000 transcripts with two- to seventeen-fold change in response to CNTF. A comparison of transcriptional profiles from Müller cells at one or three days after CNTF treatment showed an increase in the number of transcribed genes as well as a change in the expression pattern. Ingenuity Pathway Analysis showed that the differentially regulated genes belong to distinct functional types such as cytokines, growth factors, G-protein coupled receptors, transporters and ion channels. Interestingly, many genes induced by CNTF were also highly expressed in reactive Müller cells from mice with inherited or experimentally induced retinal degeneration. Further analysis of gene profiles revealed 20–30% overlap in the transcription pattern among Müller cells, astrocytes and the RPE.Conclusions/SignificanceOur studies provide novel molecular insights into biological functions of Müller glial cells in mediating cytokine response. We suggest that CNTF remodels the gene expression profile of Müller cells leading to induction of networks associated with transcription, cell cycle regulation and inflammatory response. CNTF also appears to function as an inducer of gliosis in the retina.
Highlights
Cytokines are secretory proteins that were initially characterized as immune modulators, but have been subsequently found to promote proliferation and differentiation in the nervous system [1]
A major hurdle in studying Ciliary neurotrophic factor (CNTF) action on Muller cells has been the lack of a reliable method to separate these cells away from retinal neurons
We report that CNTF induces rapid and extensive changes in the transcriptional profile of Muller cells in vivo
Summary
Cytokines are secretory proteins that were initially characterized as immune modulators, but have been subsequently found to promote proliferation and differentiation in the nervous system [1]. CNTF promotes the survival of a variety of neurons and oligodendrocytes, and induces neurite outgrowth and axon regeneration in both developing and mature nervous system [13,14,15,16,17,18]. It appears to be an effective neuroprotective agent in animal models of CNS neurodegenerative diseases [19]. Ciliary neurotrophic factor (CNTF), a member of the interleukin-6 cytokine family, has been implicated in the development, differentiation and survival of retinal neurons. We have examined gene expression dynamics of purified Muller (glial) cells exposed to CNTF in vivo
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