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Unique aspects of transcriptional regulation in neurons--nuances in NFkappaB and Sp1-related factors.

Mao XR, Moerman-Herzog AM, Chen Y, Barger SW - J Neuroinflammation (2009)

Bottom Line: These studies led us to conclude that this population of cells is nearly incapable of activating the NFkappaB that is nonetheless expressed at reasonable levels.A subset of the kappaB cis elements are instead bound by members of the Sp1 family in neurons.Also surprising was our discovery that Sp1 itself, typically described as ubiquitous, is severely restricted in expression within forebrain neurons; Sp4 seems to be substituted during neuronal differentiation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110, USA. maox@morpheus.wustl.edu

ABSTRACT
The unique physiology and function of neurons create differences in their cellular physiology, including their regulation of gene expression. We began several years ago exploring the relationships between the NFkappaB transcription factor, neuronal survival, and glutamate receptor activation in telencephalic neurons. These studies led us to conclude that this population of cells is nearly incapable of activating the NFkappaB that is nonetheless expressed at reasonable levels. A subset of the kappaB cis elements are instead bound by members of the Sp1 family in neurons. Also surprising was our discovery that Sp1 itself, typically described as ubiquitous, is severely restricted in expression within forebrain neurons; Sp4 seems to be substituted during neuronal differentiation. These findings and their implications for neuronal differentiation--as well as potential dedifferentiation during degenerative processes--are discussed here.

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Induction of neuronal expression of cyclin D1 in βAPP-deficient mice. Brain sections from wild-type ("WT") and βAPP-knockout ("APP-KO") mice were subjected to immunofluorescence detection of cyclin D1 (green). The sections were counterstained with DAPI to visualize nuclei (blue). Representative images are shown. The pixel intensity of specific staining was randomly sampled in the CA1 and dentate cell body layer. The mean values and standard errors are shown in graphically. Statistical comparison between the two genotypes by t-test indicated p < 0.05 (n = 4) in each hippocampal region.
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Figure 7: Induction of neuronal expression of cyclin D1 in βAPP-deficient mice. Brain sections from wild-type ("WT") and βAPP-knockout ("APP-KO") mice were subjected to immunofluorescence detection of cyclin D1 (green). The sections were counterstained with DAPI to visualize nuclei (blue). Representative images are shown. The pixel intensity of specific staining was randomly sampled in the CA1 and dentate cell body layer. The mean values and standard errors are shown in graphically. Statistical comparison between the two genotypes by t-test indicated p < 0.05 (n = 4) in each hippocampal region.

Mentions: As a specific neuroinflammatory condition, Alzheimer's disease might hold relevance for the unique expression and regulation of transcription factors we have found in neurons. We recently conducted an analysis of βAPP expression in normal aging and Alzheimer's disease [81]. These studies documented a glutamate-triggered induction of βAPP expression that is dependent upon the product of the ε3 allele of apolipoprotein E (ApoE3). (Possession of the major alternative allele in humans, ApoE4, is associated with a dramatically increased risk for Alzheimer's disease.) Moreover, our findings indicated that this glutamate→ApoE3→βAPP axis becomes uncoupled in the early stages of Alzheimer pathogenesis. ApoE levels continue to rise with advancing Alzheimer pathology, but de novo expression of βAPP in neuronal somata is dramatically depleted. To test the consequences of this loss of βAPP, we examined βAPP-knockout mice [95]. Neurons in the brains of these mice showed elevated expression of cyclins D1 (Figure 7) and E1 (not shown), which have promoters that are responsive to Sp1. Such ectopic expression of cell cycle markers in post-mitotic neurons is a curious component of pathology found in Alzheimer's and other neurodegenerative conditions and one that appears to trigger apoptosis [96]. It is possible that this phenomenon involves derangement of the Sp4:Sp1 ratio in stressed neurons.


Unique aspects of transcriptional regulation in neurons--nuances in NFkappaB and Sp1-related factors.

Mao XR, Moerman-Herzog AM, Chen Y, Barger SW - J Neuroinflammation (2009)

Induction of neuronal expression of cyclin D1 in βAPP-deficient mice. Brain sections from wild-type ("WT") and βAPP-knockout ("APP-KO") mice were subjected to immunofluorescence detection of cyclin D1 (green). The sections were counterstained with DAPI to visualize nuclei (blue). Representative images are shown. The pixel intensity of specific staining was randomly sampled in the CA1 and dentate cell body layer. The mean values and standard errors are shown in graphically. Statistical comparison between the two genotypes by t-test indicated p < 0.05 (n = 4) in each hippocampal region.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2693111&req=5

Figure 7: Induction of neuronal expression of cyclin D1 in βAPP-deficient mice. Brain sections from wild-type ("WT") and βAPP-knockout ("APP-KO") mice were subjected to immunofluorescence detection of cyclin D1 (green). The sections were counterstained with DAPI to visualize nuclei (blue). Representative images are shown. The pixel intensity of specific staining was randomly sampled in the CA1 and dentate cell body layer. The mean values and standard errors are shown in graphically. Statistical comparison between the two genotypes by t-test indicated p < 0.05 (n = 4) in each hippocampal region.
Mentions: As a specific neuroinflammatory condition, Alzheimer's disease might hold relevance for the unique expression and regulation of transcription factors we have found in neurons. We recently conducted an analysis of βAPP expression in normal aging and Alzheimer's disease [81]. These studies documented a glutamate-triggered induction of βAPP expression that is dependent upon the product of the ε3 allele of apolipoprotein E (ApoE3). (Possession of the major alternative allele in humans, ApoE4, is associated with a dramatically increased risk for Alzheimer's disease.) Moreover, our findings indicated that this glutamate→ApoE3→βAPP axis becomes uncoupled in the early stages of Alzheimer pathogenesis. ApoE levels continue to rise with advancing Alzheimer pathology, but de novo expression of βAPP in neuronal somata is dramatically depleted. To test the consequences of this loss of βAPP, we examined βAPP-knockout mice [95]. Neurons in the brains of these mice showed elevated expression of cyclins D1 (Figure 7) and E1 (not shown), which have promoters that are responsive to Sp1. Such ectopic expression of cell cycle markers in post-mitotic neurons is a curious component of pathology found in Alzheimer's and other neurodegenerative conditions and one that appears to trigger apoptosis [96]. It is possible that this phenomenon involves derangement of the Sp4:Sp1 ratio in stressed neurons.

Bottom Line: These studies led us to conclude that this population of cells is nearly incapable of activating the NFkappaB that is nonetheless expressed at reasonable levels.A subset of the kappaB cis elements are instead bound by members of the Sp1 family in neurons.Also surprising was our discovery that Sp1 itself, typically described as ubiquitous, is severely restricted in expression within forebrain neurons; Sp4 seems to be substituted during neuronal differentiation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110, USA. maox@morpheus.wustl.edu

ABSTRACT
The unique physiology and function of neurons create differences in their cellular physiology, including their regulation of gene expression. We began several years ago exploring the relationships between the NFkappaB transcription factor, neuronal survival, and glutamate receptor activation in telencephalic neurons. These studies led us to conclude that this population of cells is nearly incapable of activating the NFkappaB that is nonetheless expressed at reasonable levels. A subset of the kappaB cis elements are instead bound by members of the Sp1 family in neurons. Also surprising was our discovery that Sp1 itself, typically described as ubiquitous, is severely restricted in expression within forebrain neurons; Sp4 seems to be substituted during neuronal differentiation. These findings and their implications for neuronal differentiation--as well as potential dedifferentiation during degenerative processes--are discussed here.

Show MeSH
Related in: MedlinePlus