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The functional genome of CA1 and CA3 neurons under native conditions and in response to ischemia.

Newrzella D, Pahlavan PS, Krüger C, Boehm C, Sorgenfrei O, Schröck H, Eisenhardt G, Bischoff N, Vogt G, Wafzig O, Rossner M, Maurer MH, Hiemisch H, Bach A, Kuschinsky W, Schneider A - BMC Genomics (2007)

Bottom Line: In the ischemic state, only about 100 genes were found to be differentially expressed in CA3 and CA1.The differences found in two morphologically very similar cell types situated next to each other in the CNS are large providing a rational basis for physiological differences.Our data generate both novel insights into the relation of the quiescent and stimulus-induced transcriptome in different cells, and provide a large dataset to the research community, both for mapping purposes, as well as for physiological and pathophysiological research.

View Article: PubMed Central - HTML - PubMed

Affiliation: Sygnis Bioscience, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. Newrzella@Sygnis.de

ABSTRACT

Background: The different physiological repertoire of CA3 and CA1 neurons in the hippocampus, as well as their differing behaviour after noxious stimuli are ultimately based upon differences in the expressed genome. We have compared CA3 and CA1 gene expression in the uninjured brain, and after cerebral ischemia using laser microdissection (LMD), RNA amplification, and array hybridization.

Results: Profiling in CA1 vs. CA3 under normoxic conditions detected more than 1000 differentially expressed genes that belong to different, physiologically relevant gene ontology groups in both cell types. The comparison of each region under normoxic and ischemic conditions revealed more than 5000 ischemia-regulated genes for each individual cell type. Surprisingly, there was a high co-regulation in both regions. In the ischemic state, only about 100 genes were found to be differentially expressed in CA3 and CA1. The majority of these genes were also different in the native state. A minority of interesting genes (e.g. inhibinbetaA) displayed divergent expression preference under native and ischemic conditions with partially opposing directions of regulation in both cell types.

Conclusion: The differences found in two morphologically very similar cell types situated next to each other in the CNS are large providing a rational basis for physiological differences. Unexpectedly, the genomic response to ischemia is highly similar in these two neuron types, leading to a substantial attenuation of functional genomic differences in these two cell types. Also, the majority of changes that exist in the ischemic state are not generated de novo by the ischemic stimulus, but are preexistant from the genomic repertoire in the native situation. This unexpected influence of a strong noxious stimulus on cell-specific gene expression differences can be explained by the activation of a cell-type independent conserved gene-expression program. Our data generate both novel insights into the relation of the quiescent and stimulus-induced transcriptome in different cells, and provide a large dataset to the research community, both for mapping purposes, as well as for physiological and pathophysiological research.

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Gene ontology analysis for CA3- and CA1-enriched genes in the native state. Bar graph depicting gene ontology (GO) analysis of the genes significantly overexpressed in CA3 or CA1. The upper part of the graph shows the GO category "Biological process", the lower part "Molecular function". GO analysis were performed using the web-based L2L tool [29]. For "Biological process" there is a strong emphasis on terms related to neuron differentiation, synaptic function, and energy metabolism in CA3, and to GABA-signaling in CA1. For "Molecular function" we find enrichment of groups like ephrin receptors, serin-type protease inhibitors, and carbohydrate moiety transfer activities. In contrast in CA1 we observe an enrichment in deglycosylating activity, ligand-gated ion channels, and sulfotransferase activity. Black, expected matches; red, observed matches.
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Figure 3: Gene ontology analysis for CA3- and CA1-enriched genes in the native state. Bar graph depicting gene ontology (GO) analysis of the genes significantly overexpressed in CA3 or CA1. The upper part of the graph shows the GO category "Biological process", the lower part "Molecular function". GO analysis were performed using the web-based L2L tool [29]. For "Biological process" there is a strong emphasis on terms related to neuron differentiation, synaptic function, and energy metabolism in CA3, and to GABA-signaling in CA1. For "Molecular function" we find enrichment of groups like ephrin receptors, serin-type protease inhibitors, and carbohydrate moiety transfer activities. In contrast in CA1 we observe an enrichment in deglycosylating activity, ligand-gated ion channels, and sulfotransferase activity. Black, expected matches; red, observed matches.

Mentions: We next performed a gene ontology analysis in the categories biological process and molecular function to systematically assess relevant funtional gene groups. Gene ontology analysis with the L2l-tool [29] demonstrated a number of functional groups that were significantly overrepresented in the CA3-enriched genes (Fig. 3). Several main topics appear evident when looking at biological process categories: First, there are several large gene groups relating to differentiation: "neuron differentiation", "nervous system development", "regulation of differentiation". Second, there is a small group of genes classified as "regulation of synaptic transmission" and similar categories. Third, there are two groups related to cellular catabolism: "alcohol catabolism" and "monosaccharide catabolism". Interestingly, there are also two categories relating to "amyloid precursor protein metabolism". For the genes relatively upregulated in CA1, we find only three categories in the biological process category enriched, most notably the "gamma-aminobutyric acid signaling pathway", with the GABA-A receptor subunits alpha 1 and 3, and beta 2, "cAMP biogenesis", and "transmembrane receptor tyrosine phosphatase signaling pathway".


The functional genome of CA1 and CA3 neurons under native conditions and in response to ischemia.

Newrzella D, Pahlavan PS, Krüger C, Boehm C, Sorgenfrei O, Schröck H, Eisenhardt G, Bischoff N, Vogt G, Wafzig O, Rossner M, Maurer MH, Hiemisch H, Bach A, Kuschinsky W, Schneider A - BMC Genomics (2007)

Gene ontology analysis for CA3- and CA1-enriched genes in the native state. Bar graph depicting gene ontology (GO) analysis of the genes significantly overexpressed in CA3 or CA1. The upper part of the graph shows the GO category "Biological process", the lower part "Molecular function". GO analysis were performed using the web-based L2L tool [29]. For "Biological process" there is a strong emphasis on terms related to neuron differentiation, synaptic function, and energy metabolism in CA3, and to GABA-signaling in CA1. For "Molecular function" we find enrichment of groups like ephrin receptors, serin-type protease inhibitors, and carbohydrate moiety transfer activities. In contrast in CA1 we observe an enrichment in deglycosylating activity, ligand-gated ion channels, and sulfotransferase activity. Black, expected matches; red, observed matches.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2194787&req=5

Figure 3: Gene ontology analysis for CA3- and CA1-enriched genes in the native state. Bar graph depicting gene ontology (GO) analysis of the genes significantly overexpressed in CA3 or CA1. The upper part of the graph shows the GO category "Biological process", the lower part "Molecular function". GO analysis were performed using the web-based L2L tool [29]. For "Biological process" there is a strong emphasis on terms related to neuron differentiation, synaptic function, and energy metabolism in CA3, and to GABA-signaling in CA1. For "Molecular function" we find enrichment of groups like ephrin receptors, serin-type protease inhibitors, and carbohydrate moiety transfer activities. In contrast in CA1 we observe an enrichment in deglycosylating activity, ligand-gated ion channels, and sulfotransferase activity. Black, expected matches; red, observed matches.
Mentions: We next performed a gene ontology analysis in the categories biological process and molecular function to systematically assess relevant funtional gene groups. Gene ontology analysis with the L2l-tool [29] demonstrated a number of functional groups that were significantly overrepresented in the CA3-enriched genes (Fig. 3). Several main topics appear evident when looking at biological process categories: First, there are several large gene groups relating to differentiation: "neuron differentiation", "nervous system development", "regulation of differentiation". Second, there is a small group of genes classified as "regulation of synaptic transmission" and similar categories. Third, there are two groups related to cellular catabolism: "alcohol catabolism" and "monosaccharide catabolism". Interestingly, there are also two categories relating to "amyloid precursor protein metabolism". For the genes relatively upregulated in CA1, we find only three categories in the biological process category enriched, most notably the "gamma-aminobutyric acid signaling pathway", with the GABA-A receptor subunits alpha 1 and 3, and beta 2, "cAMP biogenesis", and "transmembrane receptor tyrosine phosphatase signaling pathway".

Bottom Line: In the ischemic state, only about 100 genes were found to be differentially expressed in CA3 and CA1.The differences found in two morphologically very similar cell types situated next to each other in the CNS are large providing a rational basis for physiological differences.Our data generate both novel insights into the relation of the quiescent and stimulus-induced transcriptome in different cells, and provide a large dataset to the research community, both for mapping purposes, as well as for physiological and pathophysiological research.

View Article: PubMed Central - HTML - PubMed

Affiliation: Sygnis Bioscience, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany. Newrzella@Sygnis.de

ABSTRACT

Background: The different physiological repertoire of CA3 and CA1 neurons in the hippocampus, as well as their differing behaviour after noxious stimuli are ultimately based upon differences in the expressed genome. We have compared CA3 and CA1 gene expression in the uninjured brain, and after cerebral ischemia using laser microdissection (LMD), RNA amplification, and array hybridization.

Results: Profiling in CA1 vs. CA3 under normoxic conditions detected more than 1000 differentially expressed genes that belong to different, physiologically relevant gene ontology groups in both cell types. The comparison of each region under normoxic and ischemic conditions revealed more than 5000 ischemia-regulated genes for each individual cell type. Surprisingly, there was a high co-regulation in both regions. In the ischemic state, only about 100 genes were found to be differentially expressed in CA3 and CA1. The majority of these genes were also different in the native state. A minority of interesting genes (e.g. inhibinbetaA) displayed divergent expression preference under native and ischemic conditions with partially opposing directions of regulation in both cell types.

Conclusion: The differences found in two morphologically very similar cell types situated next to each other in the CNS are large providing a rational basis for physiological differences. Unexpectedly, the genomic response to ischemia is highly similar in these two neuron types, leading to a substantial attenuation of functional genomic differences in these two cell types. Also, the majority of changes that exist in the ischemic state are not generated de novo by the ischemic stimulus, but are preexistant from the genomic repertoire in the native situation. This unexpected influence of a strong noxious stimulus on cell-specific gene expression differences can be explained by the activation of a cell-type independent conserved gene-expression program. Our data generate both novel insights into the relation of the quiescent and stimulus-induced transcriptome in different cells, and provide a large dataset to the research community, both for mapping purposes, as well as for physiological and pathophysiological research.

Show MeSH
Related in: MedlinePlus