Clustered Gene Expression Changes Flank Targeted Gene Loci in Knockout Mice

Valor, Luis M.; Grant, Seth G. N.

doi:10.1371/journal.pone.0001303

Cited by 19 publications

(18 citation statements)

References 40 publications

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“…Valor and Grant have shown that remnant 129/Ola sequences may lead to subtle gene-expression differences in transgenic mouse models because of mixed genetic differences surrounding the gene that was modified during the transgenesis process (12). When comparing expression profiles from our mutant KI and wild-type mice, we indeed observed an overrepresentation of DEGs located in close proximity to the mutated Cacna1a gene.…”

Section: à3mentioning

confidence: 58%

RNA expression profiling in brains of familial hemiplegic migraine type 1 knock-in mice

et al. 2013

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Background: Various CACNA1A missense mutations cause familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of migraine with aura. FHM1 mutation R192Q is associated with pure hemiplegic migraine, whereas the S218L mutation causes hemiplegic migraine, cerebellar ataxia, seizures, and mild head trauma-induced brain edema. Transgenic knock-in (KI) migraine mouse models were generated that carried either the FHM1 R192Q or the S218L mutation and were shown to exhibit increased Ca V 2.1 channel activity. Here we investigated their cerebellar and caudal cortical transcriptome. Methods: Caudal cortical and cerebellar RNA expression profiles from mutant and wild-type mice were studied using microarrays. Respective brain regions were selected based on their relevance to migraine aura and ataxia. Relevant expression changes were further investigated at RNA and protein level by quantitative polymerase chain reaction (qPCR) and/or immunohistochemistry, respectively. Results: Expression differences in the cerebellum were most pronounced in S218L mice. Particularly, tyrosine hydroxylase, a marker of delayed cerebellar maturation, appeared strongly upregulated in S218L cerebella. In contrast, only minimal expression differences were observed in the caudal cortex of either mutant mice strain. Conclusion: Despite pronounced consequences of migraine gene mutations at the neurobiological level, changes in cortical RNA expression in FHM1 migraine mice compared to wild-type are modest. In contrast, pronounced RNA expression changes are seen in the cerebellum of S218L mice and may explain their cerebellar ataxia phenotype.

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Section: à3mentioning

confidence: 58%

RNA expression profiling in brains of familial hemiplegic migraine type 1 knock-in mice

et al. 2013

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“…Generally, the genes linked to the targeted locus are not a problem. However, when the mutation affects flanking genes or vice versa, the result of the analysis of the null mutation can lead to unexpected conclusions Valor and Grant, 2007;Wolfer et al, 2002).…”

Section: The Dilemmamentioning

confidence: 99%

Genetic Background and the Dilemma of Translating Mouse Studies to Humans

2008

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“…Nonetheless, it remains possible that RASGRP2 dysfunction may indeed produce LAD3-like symptoms since both proteins operate in the same signaling axis (Figure 1) and mice lacking Rasgrp2 have an LAD3-like phenotype. 3 Owing to their chromosomal proximity (within ~ 600 Mbp on mouse chromosome 19), it is also possible that the knockout mutation in the mouse Rasgrp2 locus might have affected the expression of neighboring genes, although these effects are usually detectable within shorter chromosomal distances 11 . Analyses of the Kindlin-3 expression levels in Rasgrp2 −/− mice will help resolve such issues.…”

Section: Three Studies Implicate Kindlin-3 a Molecule That Mediates mentioning

confidence: 99%