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Ciliary neurotrophic factor induces genes associated with inflammation and gliosis in the retina: a gene profiling study of flow-sorted, Müller cells.

Xue W, Cojocaru RI, Dudley VJ, Brooks M, Swaroop A, Sarthy VP - PLoS ONE (2011)

Bottom Line: 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.Further analysis of gene profiles revealed 20-30% overlap in the transcription pattern among Müller cells, astrocytes and the RPE.Our studies provide novel molecular insights into biological functions of Müller glial cells in mediating cytokine response.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Northwestern University Feinberg Medical School, Chicago, Illinois, United States of America.

ABSTRACT

Background: Ciliary 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 findings: Müller 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/significance: Our 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.

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Related in: MedlinePlus

Overlapping genes in transcription profiles from Müller cells, astrocytes and retinal pigment epithelium (RPE).Intensity signals for the top 2000 probes were used to generate sets of overlapping genes. The astrocyte and RPE transcriptome data are derived from published studies (56,57). Müller cell data represent signals from cells not exposed to CNTF. (a) The diagram shows that 381 transcripts were common to the three cell types, while 642 were shared between Müller cells and astrocytes, 565 between Müller cells and the RPE, and 604 between astrocytes and RPE. (b) Diagram showing overlap of transcripts among astrocytes, Muller cells and neurons. The neuron transcriptome data was obtained from a published study (56).
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pone-0020326-g006: Overlapping genes in transcription profiles from Müller cells, astrocytes and retinal pigment epithelium (RPE).Intensity signals for the top 2000 probes were used to generate sets of overlapping genes. The astrocyte and RPE transcriptome data are derived from published studies (56,57). Müller cell data represent signals from cells not exposed to CNTF. (a) The diagram shows that 381 transcripts were common to the three cell types, while 642 were shared between Müller cells and astrocytes, 565 between Müller cells and the RPE, and 604 between astrocytes and RPE. (b) Diagram showing overlap of transcripts among astrocytes, Muller cells and neurons. The neuron transcriptome data was obtained from a published study (56).

Mentions: Müller (glial) cells perform metabolic functions similar to astrocytes and RPE [41], [57]. To determine whether this similarity is also reflected in the gene expression profiles of these cell types, we compared the top 2000 highly expressed transcripts from Müller cells and astrocytes (Table S1), using previously published astrocyte transcriptome data from postnatal day-17 mice [58]. As shown in Figure 6, 642 genes were common to Müller cells and astrocytes yielding a 32% overlap in transcriptional pattern. In comparison, Müller cells and retinal pigment epithelial cells (RPE) have 565 genes in common. The RPE transcriptome data were obtained from a recent publication [59]. There is a 14% overlap (381 genes) in highly expressed genes among the three different cell types (Fig. 6a). When compared with transcriptional profiles of neurons, there was an overlap of 27% (Fig. 6b, 58).


Ciliary neurotrophic factor induces genes associated with inflammation and gliosis in the retina: a gene profiling study of flow-sorted, Müller cells.

Xue W, Cojocaru RI, Dudley VJ, Brooks M, Swaroop A, Sarthy VP - PLoS ONE (2011)

Overlapping genes in transcription profiles from Müller cells, astrocytes and retinal pigment epithelium (RPE).Intensity signals for the top 2000 probes were used to generate sets of overlapping genes. The astrocyte and RPE transcriptome data are derived from published studies (56,57). Müller cell data represent signals from cells not exposed to CNTF. (a) The diagram shows that 381 transcripts were common to the three cell types, while 642 were shared between Müller cells and astrocytes, 565 between Müller cells and the RPE, and 604 between astrocytes and RPE. (b) Diagram showing overlap of transcripts among astrocytes, Muller cells and neurons. The neuron transcriptome data was obtained from a published study (56).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102695&req=5

pone-0020326-g006: Overlapping genes in transcription profiles from Müller cells, astrocytes and retinal pigment epithelium (RPE).Intensity signals for the top 2000 probes were used to generate sets of overlapping genes. The astrocyte and RPE transcriptome data are derived from published studies (56,57). Müller cell data represent signals from cells not exposed to CNTF. (a) The diagram shows that 381 transcripts were common to the three cell types, while 642 were shared between Müller cells and astrocytes, 565 between Müller cells and the RPE, and 604 between astrocytes and RPE. (b) Diagram showing overlap of transcripts among astrocytes, Muller cells and neurons. The neuron transcriptome data was obtained from a published study (56).
Mentions: Müller (glial) cells perform metabolic functions similar to astrocytes and RPE [41], [57]. To determine whether this similarity is also reflected in the gene expression profiles of these cell types, we compared the top 2000 highly expressed transcripts from Müller cells and astrocytes (Table S1), using previously published astrocyte transcriptome data from postnatal day-17 mice [58]. As shown in Figure 6, 642 genes were common to Müller cells and astrocytes yielding a 32% overlap in transcriptional pattern. In comparison, Müller cells and retinal pigment epithelial cells (RPE) have 565 genes in common. The RPE transcriptome data were obtained from a recent publication [59]. There is a 14% overlap (381 genes) in highly expressed genes among the three different cell types (Fig. 6a). When compared with transcriptional profiles of neurons, there was an overlap of 27% (Fig. 6b, 58).

Bottom Line: 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.Further analysis of gene profiles revealed 20-30% overlap in the transcription pattern among Müller cells, astrocytes and the RPE.Our studies provide novel molecular insights into biological functions of Müller glial cells in mediating cytokine response.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Northwestern University Feinberg Medical School, Chicago, Illinois, United States of America.

ABSTRACT

Background: Ciliary 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 findings: Müller 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/significance: Our 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.

Show MeSH
Related in: MedlinePlus