Restricted transgene expression in the brain with cell-type specific neuronal promoters.

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State: Public
Version: author
Serval ID
serval:BIB_B17434CC555F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Restricted transgene expression in the brain with cell-type specific neuronal promoters.
Journal
Human Gene Therapy Methods
Author(s)
Delzor A., Dufour N., Petit F., Guillermier M., Houitte D., Auregan G., Brouillet E., Hantraye P., Déglon N.
ISSN
1946-6544 (Electronic)
Publication state
Published
Issued date
2012
Peer-reviewed
Oui
Volume
23
Number
4
Pages
242-254
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Abstract
Tissue-targeted expression is of major interest for studying the contribution of cellular subpopulations to neurodegenerative diseases. However, in vivo methods to investigate this issue are limited. Here, we report an analysis of the cell specificity of expression of fluorescent reporter genes driven by six neuronal promoters, with the ubiquitous phosphoglycerate kinase 1 (PGK) promoter used as a reference. Quantitative analysis of AcGFPnuc expression in the striatum and hippocampus of rodents showed that all lentiviral vectors (LV) exhibited a neuronal tropism; however, there was substantial diversity of transcriptional activity and cell-type specificity of expression. The promoters with the highest activity were those of the 67 kDa glutamic acid decarboxylase (GAD67), homeobox Dlx5/6, glutamate receptor 1 (GluR1), and preprotachykinin 1 (Tac1) genes. Neuron-specific enolase (NSE) and dopaminergic receptor 1 (Drd1a) promoters showed weak activity, but the integration of an amplification system into the LV overcame this limitation. In the striatum, the expression profiles of Tac1 and Drd1a were not limited to the striatonigral pathway, whereas in the hippocampus, Drd1a and Dlx5/6 showed the expected restricted pattern of expression. Regulation of the Dlx5/6 promoter was observed in a disease condition, whereas Tac1 activity was unaffected. These vectors provide safe tools that are more selective than others available, for the administration of therapeutic molecules in the central nervous system (CNS). Nevertheless, additional characterization of regulatory elements in neuronal promoters is still required.
Keywords
Animals, Brain/metabolism, Brain/pathology, Genes, Reporter, Genetic Vectors/genetics, Genetic Vectors/metabolism, Glutamate Decarboxylase/genetics, Glutamate Decarboxylase/metabolism, Hippocampus/metabolism, Homeodomain Proteins/genetics, Homeodomain Proteins/metabolism, Lentivirus/genetics, Male, Mice, Neurons/metabolism, Neurons/pathology, Phosphoglycerate Kinase/genetics, Phosphoglycerate Kinase/metabolism, Phosphopyruvate Hydratase/genetics, Phosphopyruvate Hydratase/metabolism, Promoter Regions, Genetic/genetics, Protein Precursors/genetics, Protein Precursors/metabolism, Rats, Receptors, AMPA/genetics, Receptors, AMPA/metabolism, Receptors, Dopamine D1/genetics, Receptors, Dopamine D1/metabolism, Tachykinins/genetics, Tachykinins/metabolism, Transcription, Genetic, Transduction, Genetic
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Create date
14/09/2012 15:26
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20/08/2019 15:20
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