Transcriptomics

Dataset Information

3

Inducible expression of PrPC in mouse skeletal muscles results in myopathy characterized by changes in gene expression


ABSTRACT: Over-expression of wild type PrP in skeletal muscles is sufficient to cause a primary myopathy with no signs of peripheral neuropathy, possibly due to accumulation of a cytotoxic truncated form of PrP and/or PrP aggregation. In this study we used DNA microarrays to identify 1499 transcripts that are temporally deregulated concomitant with inducible PrPC over-expression in the skeletal muscles of transgenic mice. Examination using microarrays revealed a transcriptional profile with both similarities and differences to previously investigated models of myopathies. Down-regulation of genes coding for the myofibrillar proteins MYH2, MYH6, MYH7, MYL2, MYL3 and up-regulation of lysosomal genes CTSS, CTSD, CTSZ, DPEP2, HEXA, HEXB and LAMP1 coincide with the observed myopathy and lysosome accumulation on over-expression of PrPC. Down-regulation of the MEF2C gene, a key regulatory transcriptional factor muscle development and remodeling of adult muscles in response to physiologic and pathologic signals, may contribute to the centrally placed nuclei in the skeletal muscles. Significantly, up-regulation of genes involved in p53 signaling and the induction of p53 protein, suggest a central role for this molecule in the myopathy. Several p53-regulated genes involved in cell cycle arrest (CDNK1A, GADD45a and GADD45b) and apoptosis (BAK1, PMAIP1, BBC3, and BAX) are induced. We suggest that PrPC over-expression in skeletal muscles, possibly in response to accumulation of a cytotoxic truncated form of PrP, causes a primary myopathy involving the induction of p53-dependent pathways. Wild type (WT), PrP-null (KO), and Tg(HQK) mice were fed food pellets either lacking or containing 6g doxycycline (Dox)/kg food to induce PrPC expression. Skeletal muscles from the quadriceps of hind legs were removed at day 0, 4, 7, 14, 30 and 60 days following administration of Dox. Total RNA was isolated from these tissues for use in subsequent microarray analysis. Mouse gene expression was analysed by two-colour microarray experiments using an inhouse manufactured 16K mouse cDNA microarray. Age matched reference mice (WT) and experimental (KO and HQK) Alexa Flour labeled aRNA were used in each competitive hybridization. Each sample was labeled individually with both Alexa Fluor 555 and 647 for subsequent dye-swapped hybridizations to account for intensity bias. 3 individual mice from each experimental group at each time point were individually processed for separate microarrays. We used the program EDGE to identify genes that were differentially expressed in mouse skeletal muscle in either transgenic HQK mice over expressing PrP, or PrP knock out (KO) mice after administration of Dox. We used a P value cut-off of 0.05 as the criteria of selection of significantly differentially expressed genes.

ORGANISM(S): Mus musculus  

SUBMITTER: Laura Landry   Stephanie A Booth  Sarah Medina  Garrett Sorensen  Jingjing Liang  Debra Parchaliuk  Qingzhong Kong 

PROVIDER: E-GEOD-12576 | ArrayExpress | 2008-08-27

SECONDARY ACCESSION(S): GSE12576PRJNA112625

REPOSITORIES: GEO, ArrayExpress

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Publications

Activation of p53-regulated pro-apoptotic signaling pathways in PrP-mediated myopathy.

Liang Jingjing J   Parchaliuk Debra D   Medina Sarah S   Sorensen Garrett G   Landry Laura L   Huang Shenghai S   Wang Meiling M   Kong Qingzhong Q   Booth Stephanie A SA  

BMC genomics 20090428


We have reported that doxycycline-induced over-expression of wild type prion protein (PrP) in skeletal muscles of Tg(HQK) mice is sufficient to cause a primary myopathy with no signs of peripheral neuropathy. The preferential accumulation of the truncated PrP C1 fragment was closely correlated with these myopathic changes. In this study we use gene expression profiling to explore the temporal program of molecular changes underlying the PrP-mediated myopathy.We used DNA microarrays, and confirmat  ...[more]

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