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Modified cell cycle status in a mouse model of altered neuronal vulnerability (slow Wallerian degeneration; Wlds).

Wishart TM, Pemberton HN, James SR, McCabe CJ, Gillingwater TH - Genome Biol. (2008)

Bottom Line: These include the following: elevated nicotinamide adenine dinucleotide (NAD) levels associated with nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1; a part of the chimeric Wlds gene); altered mRNA expression levels of genes such as pituitary tumor transforming gene 1 (Pttg1); changes in the location/activity of the ubiquitin-proteasome machinery via binding to valosin-containing protein (VCP/p97); and modified synaptic expression of proteins such as ubiquitin-activating enzyme E1 (Ube1).We show that previous reports of diverse changes occurring downstream from Wlds expression converge upon modifications in cell cycle status.These data suggest a strong correlation between modified cell cycle pathways and altered vulnerability of axonal and synaptic compartments in postmitotic, terminally differentiated neurons.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Integrative Physiology, University of Edinburgh Medical School, Edinburgh, UK.

ABSTRACT

Background: Altered neuronal vulnerability underlies many diseases of the human nervous system, resulting in degeneration and loss of neurons. The neuroprotective slow Wallerian degeneration (Wlds) mutation delays degeneration in axonal and synaptic compartments of neurons following a wide range of traumatic and disease-inducing stimuli, providing a powerful experimental tool with which to investigate modulation of neuronal vulnerability. Although the mechanisms through which Wlds confers neuroprotection remain unclear, a diverse range of downstream modifications, incorporating several genes/pathways, have been implicated. These include the following: elevated nicotinamide adenine dinucleotide (NAD) levels associated with nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1; a part of the chimeric Wlds gene); altered mRNA expression levels of genes such as pituitary tumor transforming gene 1 (Pttg1); changes in the location/activity of the ubiquitin-proteasome machinery via binding to valosin-containing protein (VCP/p97); and modified synaptic expression of proteins such as ubiquitin-activating enzyme E1 (Ube1).

Results: Wlds expression in mouse cerebellum and HEK293 cells induced robust increases in a broad spectrum of cell cycle-related genes. Both NAD-dependent and Pttg1-dependent pathways were responsible for mediating different subsets of these alterations, also incorporating changes in VCP/p97 localization and Ube1 expression. Cell proliferation rates were not modified by Wlds, suggesting that later mitotic phases of the cell cycle remained unaltered. We also demonstrate that Wlds concurrently altered endogenous cell stress pathways.

Conclusion: We report a novel cellular phenotype in cells with altered neuronal vulnerability. We show that previous reports of diverse changes occurring downstream from Wlds expression converge upon modifications in cell cycle status. These data suggest a strong correlation between modified cell cycle pathways and altered vulnerability of axonal and synaptic compartments in postmitotic, terminally differentiated neurons.

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Related in: MedlinePlus

Widespread alterations in cell stress genes in uninjured/untreated Wlds mouse cerebellum in vivo. Three-dimensional bar chart taken from SuperArray analysis software (cell stress SuperArray; see Materials and methods) showing fold difference in expression levels for 84 cell stress related genes comparing wild-type cerebellum (control sample) with Wlds cerebellum (test sample). Individual genes with a greater than twofold expression change can be found in Table 3.
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Figure 12: Widespread alterations in cell stress genes in uninjured/untreated Wlds mouse cerebellum in vivo. Three-dimensional bar chart taken from SuperArray analysis software (cell stress SuperArray; see Materials and methods) showing fold difference in expression levels for 84 cell stress related genes comparing wild-type cerebellum (control sample) with Wlds cerebellum (test sample). Individual genes with a greater than twofold expression change can be found in Table 3.

Mentions: Changes in cell cycle status in terminally differentiated neurons are often associated with corresponding changes in cell stress pathways [58-60]. To examine whether cell stress pathways were also altered in Wlds-expressing cells, we used cell stress pathway-specific RT2 profiler PCR arrays (see Materials and methods [below]) to compare mRNA levels in the cerebellum of wild-type and Wlds mice (Figure 12). Fourteen out of the 84 genes contained on the array were modified greater than twofold by Wlds, showing that a subset of cell stress pathways are also modified in Wlds (Figure 12 and Table 3). In contrast to the results from cell cycle arrays, however, Wlds neurons revealed both increases and decreases across a range of different cell stress proteins.


Modified cell cycle status in a mouse model of altered neuronal vulnerability (slow Wallerian degeneration; Wlds).

Wishart TM, Pemberton HN, James SR, McCabe CJ, Gillingwater TH - Genome Biol. (2008)

Widespread alterations in cell stress genes in uninjured/untreated Wlds mouse cerebellum in vivo. Three-dimensional bar chart taken from SuperArray analysis software (cell stress SuperArray; see Materials and methods) showing fold difference in expression levels for 84 cell stress related genes comparing wild-type cerebellum (control sample) with Wlds cerebellum (test sample). Individual genes with a greater than twofold expression change can be found in Table 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2481432&req=5

Figure 12: Widespread alterations in cell stress genes in uninjured/untreated Wlds mouse cerebellum in vivo. Three-dimensional bar chart taken from SuperArray analysis software (cell stress SuperArray; see Materials and methods) showing fold difference in expression levels for 84 cell stress related genes comparing wild-type cerebellum (control sample) with Wlds cerebellum (test sample). Individual genes with a greater than twofold expression change can be found in Table 3.
Mentions: Changes in cell cycle status in terminally differentiated neurons are often associated with corresponding changes in cell stress pathways [58-60]. To examine whether cell stress pathways were also altered in Wlds-expressing cells, we used cell stress pathway-specific RT2 profiler PCR arrays (see Materials and methods [below]) to compare mRNA levels in the cerebellum of wild-type and Wlds mice (Figure 12). Fourteen out of the 84 genes contained on the array were modified greater than twofold by Wlds, showing that a subset of cell stress pathways are also modified in Wlds (Figure 12 and Table 3). In contrast to the results from cell cycle arrays, however, Wlds neurons revealed both increases and decreases across a range of different cell stress proteins.

Bottom Line: These include the following: elevated nicotinamide adenine dinucleotide (NAD) levels associated with nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1; a part of the chimeric Wlds gene); altered mRNA expression levels of genes such as pituitary tumor transforming gene 1 (Pttg1); changes in the location/activity of the ubiquitin-proteasome machinery via binding to valosin-containing protein (VCP/p97); and modified synaptic expression of proteins such as ubiquitin-activating enzyme E1 (Ube1).We show that previous reports of diverse changes occurring downstream from Wlds expression converge upon modifications in cell cycle status.These data suggest a strong correlation between modified cell cycle pathways and altered vulnerability of axonal and synaptic compartments in postmitotic, terminally differentiated neurons.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Integrative Physiology, University of Edinburgh Medical School, Edinburgh, UK.

ABSTRACT

Background: Altered neuronal vulnerability underlies many diseases of the human nervous system, resulting in degeneration and loss of neurons. The neuroprotective slow Wallerian degeneration (Wlds) mutation delays degeneration in axonal and synaptic compartments of neurons following a wide range of traumatic and disease-inducing stimuli, providing a powerful experimental tool with which to investigate modulation of neuronal vulnerability. Although the mechanisms through which Wlds confers neuroprotection remain unclear, a diverse range of downstream modifications, incorporating several genes/pathways, have been implicated. These include the following: elevated nicotinamide adenine dinucleotide (NAD) levels associated with nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1; a part of the chimeric Wlds gene); altered mRNA expression levels of genes such as pituitary tumor transforming gene 1 (Pttg1); changes in the location/activity of the ubiquitin-proteasome machinery via binding to valosin-containing protein (VCP/p97); and modified synaptic expression of proteins such as ubiquitin-activating enzyme E1 (Ube1).

Results: Wlds expression in mouse cerebellum and HEK293 cells induced robust increases in a broad spectrum of cell cycle-related genes. Both NAD-dependent and Pttg1-dependent pathways were responsible for mediating different subsets of these alterations, also incorporating changes in VCP/p97 localization and Ube1 expression. Cell proliferation rates were not modified by Wlds, suggesting that later mitotic phases of the cell cycle remained unaltered. We also demonstrate that Wlds concurrently altered endogenous cell stress pathways.

Conclusion: We report a novel cellular phenotype in cells with altered neuronal vulnerability. We show that previous reports of diverse changes occurring downstream from Wlds expression converge upon modifications in cell cycle status. These data suggest a strong correlation between modified cell cycle pathways and altered vulnerability of axonal and synaptic compartments in postmitotic, terminally differentiated neurons.

Show MeSH
Related in: MedlinePlus