Unknown,Transcriptomics,Genomics,Proteomics

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Gene Expression profiling of transgenic mice expressing the genetically encoded calcium indicator TN-XXL in muscle and brain tissues

ABSTRACT: Engineering of genetically encoded calcium indicators predominantly focused on optimizing fluorescence changes, but effects of indicator expression on host organisms have largely not been addressed. Here, we report biocompatibility and wide-spread functional expression of the genetically encoded calcium indicator TN-XXL in a transgenic mouse model. To validate the model and to characterize potential effects of indicator expression we assessed both indicator function and a variety of host parameters such as anatomy, physiology, behavior and gene expression profiles in these mice. We also demonstrate the usefulness of primary cell types and organ explants prepared from these mice for imaging applications. While we do find mild signatures of indicator expression that may guide further indicator development the M-bM-^@M-^\greenM-bM-^@M-^] indicator mice generated provide a well characterized resource of primary cells and tissues for in vitro and in vivo calcium imaging applications. Using expression profiling we could detect a number of transcripts regulated predominantly in heart and skeletal muscle of TN-XXL transgenic mice but only very few showed a level of regulation of a factor of two or higher and thus the majority of these changes were considered physiologically irrelevant. Remarkably this regulation occurred in skeletal and cardiac muscle, but not in brain. This suggests that skeletal muscle TnC as calcium sensing moiety within the indicator may be bio-orthogonal in brain but may lose some of this advantage in muscle tissue where it is derived from. Factorial design comparing transgenic mice with wild type littermates in three different tissues (hippocampus, skeletal and heart muscle)

ORGANISM(S): Mus musculus

SUBMITTER: Stephan Direnberger

PROVIDER: E-GEOD-39632 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Transgenic overexpression of Galgt2 in the skeletal muscles of mdx mice inhibits the development of disease pathology associated with muscular dystrophy. This is the case both in transgenic mice, where Galgt2 overexpression occurs from embryonic timepoints onward and in mdx mice where Galgt2 is overexpressed in the early postnatal period using Adeno-associated virus (AAV). Here, we use gene expression profiling to compare transcriptional changes resulting from embryonic and postnatal Galgt2 overexpression in mdx skeletal muscle. A surprising number of changes were in genes known to ameliorate muscular dystrophy when overexpressed (agrin, integrin alpha 7, ADAM12, Bcl2) or to cause muscular dystrophy when mutated (collagen VI (alpha1,alpha2), plectin 1, dystroglycan, selenoprotein N1, integrin alpha7, biglycan, dysferlin). Several genes involved in calcium homeostasis were also changed. In Galgt2 transgenic mice, where embryonic overexpression of Galgt2 in skeletal muscles alters neuromuscular development and muscle growth, the number of gene expression changes was vastly greater, however, 14% of genes altered in postnatal AAV-Galgt2 infected mdx muscles were also changed with embryonic overexpression. These experiments suggest that postnatal overexpression of Galgt2 inhibits muscular dystrophy in mdx mice via induction of a group of genes that, in aggregate, can govern membrane stability, membrane repair, calcium homeostasis, and apoptosis. Transgenic overexpression of Galgt2 in the skeletal muscles of mdx mice inhibits the development of disease pathology associated with muscular dystrophy. This is the case both in transgenic mice, where Galgt2 overexpression occurs from embryonic timepoints onward and in mdx mice where Galgt2 is overexpressed in the early postnatal period using Adeno-associated virus (AAV). Here, we use gene expression profiling to compare transcriptional changes resulting from embryonic and postnatal Galgt2 overexpression in mdx skeletal muscle. A surprising number of changes were in genes known to ameliorate muscular dystrophy when overexpressed (agrin, integrin alpha7, ADAM12, Bcl2) or to cause muscular dystrophy when mutated (collagen VI (alpha1,alpha2), plectin 1, dystroglycan, selenoprotein N1, integrin alpha7, biglycan, dysferlin). Several genes involved in calcium homeostasis were also changed. In Galgt2 transgenic mice, where embryonic overexpression of Galgt2 in skeletal muscles alters neuromuscular development and muscle growth, the number of gene expression changes was vastly greater, however, 14% of genes altered in postnatal AAV-Galgt2 infected mdx muscles were also changed with embryonic overexpression. These experiments suggest that postnatal overexpression of Galgt2 inhibits muscular dystrophy in mdx mice via induction of a group of genes that, in aggregate, can govern membrane stability, membrane repair, calcium homeostasis, and apoptosis. Experiment Overall Design: Microarrays were done in three groups at a time. 1) Transgenic Overexpression of Galgt2 - comprised to Wild Type (WT), Galgt2 Transgenic (CT), Dystrophin-Deficient (mdx), and Galgt2 Transgenic and Dystrophin-Deficient (CTmdx) each in duplicate 2) AAV-Mediated Galgt2 Gene Delivery in to the mdx gastrocnemius muscle in the postnatal period - comprised of AAVGalgt2 and PBS each in duplicate, and 3) Myoblasts and myotubes - comptised of one sample each of C1C12 myoblasts and myotubes, C2C12 myoblasts and myotubes stably transfected with Galgt2

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Gene Expression profiling of transgenic mice expressing the genetically encoded calcium indicator TN-XXL in muscle and brain tissues

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