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RNAseq analysis of gene expression profiles in a mouse model of tuberous sclerosis

ABSTRACT: We have generated a tuberous sclerosis complex (TSC) mouse model through mouse Gfap-Cre mediated conditional knockout of Tsc1 gene. Tsc1 depletion occurs in most astrocytes and a fraction of upper cortical and hippocampal neurons. The mice develop spontaneous seizures after 10 weeks of age. To determine the effect of Tsc1 deficiency on astrocytes, we compared astrocyte gene expressio profiles between mGfap-Cre:Tsc1CKO and littermate control mice at 4 weeks and 15 weeks of age. At 4 weeks, mGfap-Cre:Tsc1CKO mice showed increased transcription of a few astrocyte genes, including Vim, Amigo2, Thbs4, Slc7a11, Gjb6 and ALDH1L1, and there were not changes in protein products of these genes. At 15 Weeks, mGfap-Cre:Tsc1CKO mice with seizures showed increased transcription of reactive astrocyte genes, including Gfap, Vim, CD44, Sparc, Serpina3n and many others. The transcriptional changes were consistent with enhanced protein levels.

ORGANISM(S): Mus musculus

PROVIDER: GSE156891 | GEO | 2021/08/31

REPOSITORIES: GEO

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Project description:GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. 2 cell types from 6 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4

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RNAseq analysis of gene expression profiles in a mouse model of tuberous sclerosis

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