B6.129(SJL)-Gnai2^tm2.1Rneu/J

Stock number: 026754
Research areas: Neurobiology Research, Research Tools

Description

These mice conditionally express the G184S mutant form of Gnai2. Exons 5-9 of the gene are flanked by loxP sites and followed downstream by additional copy of exon 5 carrying the G184S mutation. Cre-mediated excision of floxed exons enables conditional expression of the mutant form of protein.

Detailed description

Gnai2 (guanine nucleotide binding protein (G protein), alpha inhibiting 2) is a member of the Gαi family of G proteins that mediate G protein coupled receptor signaling. This family of genes plays an important role in regulating inflammation, cardiovascular function, endocrine signaling, drug abuse, and anxiety/depression–related behaviors. Signaling through Gαi is suppressed by “regulator of G protein signaling” (RGS) proteins which accelerate the hydrolysis of Gαi-bound guanine nucleotide triphosphate (GTP). A G184S mutation in Gnai2 blocks RGS binding and activity.

In this strain, exons 5-9 of the gene are flanked by loxP sites and followed downstream by additional copy of exon 5 carrying the G184S mutation. Expression of wildtype protein is replaced by that of the mutant form upon cre-mediated excision of the floxed exons.

When crossed these with a tamoxifen-inducible Cre-ER strain (e.g. Stock No. 008463), the G184S mutant form of the gene is expressed upon treatment with tamoxifen.

Mice lacking interactions between GNAI2 and RGS exhibit a number of cardiac phenotypes including enhanced carbachol-induced bradycardia, enhanced isoproterenol-induced cardiac fibrosis, and premature death in a dilated cardiomyopathy model. Hearts from both homozygous and heterozygous G184S mutant mice also exhibit smaller infarcts and better recovery of cardiac contractile function following an ischemic insult. Genetic disruption of interactions between GNAI2 and endogenous RGS proteins also produces several non-cardiac phenotypic changes including antidepressant-like behavior, resistance to high fat diet-induced weight gain, decreased body fat, and protection from the development of insulin resistance.

Development

Exons 5-9 of the gene are flanked by loxP sites and followed downstream by additional copy of exon 5 carrying a G184S mutation. An FRT-flanked neomycin resistance cassette was placed 3'. The mutation was created in 129-derived embryonic stem (ES) cells. The neomycin cassette was excised from resultant animals through crosses with an ACTB-Flp recombinase-expressing strain (see Stock No. 005703). This line was backcrossed to C57BL/6J for 5 generations by the donating laboratory.

Allele

Symbol: Gnai2^tm2.1Rneu
Name: targeted mutation 2.1, Richard R Neubig
MGI accession ID: MGI:5614236
Generation method: Targeted
Attributes: Conditional ready (e.g. floxed); No functional change
Synonyms: Galphai2^fl-G184S
Marker symbol: Gnai2
Marker name: guanine nucleotide binding protein (G protein), alpha inhibiting 2
Marker synonyms: Galphai2; Gia; GIP; Gnai-2; GNAI2B; H_LUCA15.1; H_LUCA16.1; Hg1c
Chromosome: 9
Strain of origin: 129/Sv
Molecular note: Exons 5-9 of the gene are flanked by loxP sites and followed downstream by an additional copy of exon 5 carrying a G184S mutation. An FRT-flanked neomycin resistance cassette was placed 3'. FLP mediated recombination removed the FRT-flanked neo cassette.