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Differential brain transcriptome of ß4 nAChR subunit-deficient mice: is it the effect of the null mutation or the background strain?

Genetic Institute, Tel Aviv Sourasky Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Studies using mice with ß4 nicotinic acetylcholine receptor (nAChR) subunit deficiency (ß4–/– mice) helped reveal the roles of this subunit in bradycardiac response to vagal stimulation, nicotine-induced seizure activity and anxiety. To identify genes that might be related to ß4-containing nAChRs activity, we compared the mRNA expression profiles of brains from ß4–/– and wild-type mice using Affymetrix U74Av2 microarray. Seventy-seven genes significantly differentiated between these two experimental groups. Of them, the two most downregulated were spastic paraplegia 21 (human) homolog (Spg21) and 6-pyruvoyl-tetrahydropterin synthase (Pts) genes. Since the targeted mutagenesis of the ß4 nAChR subunit was done by using two mouse strains, 129SvEv and C57BL/6J, it is possible that the genes closely linked to the mutated ß4 gene represent the 129SvEv allele and not the control C57BL/6J-driven allele. We examined this possibility by using public database and quantitative RT-PCR. The expression levels of Spg21 and Pts genes that, like the ß4 gene, are localized on mouse chromosome 9, as well as the expression levels of other genes located on this chromosome, were dependent on the mouse background strain. The 67 differentially expressed genes that are not located on chromosome 9 were further analyzed for overrepresented functional annotations and transcription regulatory elements compared with the entire microarray. Genes encoding for proteins involved in tyrosine phosphatase activity, calcium ion binding, cell growth and/or maintenance, and chromosome organization were overrepresented. Our data enhance the understanding of the molecular interactions involved in the ß4 nAChR subunit function. They also emphasize the need for careful interpretation of expression microarray studies done on genetically manipulated animals.

nicotinic acetylcholine receptor; ß4 subunit; knockout mice; microarray; gene expression; background mouse strain

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				M. Kedmi and A. Orr-Urtreger Expression changes in mouse brains following nicotine-induced seizures: the modulation of transcription factor networks Physiol Genomics, August 20, 2007; 30(3): 242 - 252. [Abstract] [Full Text] [PDF]