In these Grn knock-out mice exons 1-4 are deleted from the targeted granulin (Grn) allele. These mice exhibit progressive frontotemporal dementia, a dysregulated inflammatory response and a high rate of pre-wean female mortality.
Aihao Ding, Weill Medical School of Cornell University
In these Grn-/- mice exons 1-4 are deleted from the targeted granulin (Grn) allele.These mice show progressive development of frontotemporal dementia-like behavior and neuropathology. This includes enhanced activation of microglia and astrocytes, and ubiquitination and cytoplasmic accumulation of phosphorylated transactivation response element DNA binding protein-43 (TDP-43) in hippocampal and thalamic neurons. By eighteen months they demonstrate impaired spatial learning and memory. Macrophages from these mice release less interleukin-10 and more inflammatory cytokines in response to microbial agents. Contrary to the increased inflammation, these mice exhibit a delay in clearing infections due to a dysregulated inflammatory response, allowing bacteria to proliferate in vivo. Activated PGRN-deficient macrophages and microglia are cytotoxic to hippocampal cells, and PGRN-deficient hippocampal slices are hypersusceptible to deprivation of oxygen and glucose. Although homozygotes are reported to be viable and fertile, significant pre-wean loss of females is observed in The Jackson Laboratory homozygous breeding colony. Of 285 pups born over 8 months, the percentage of males weaned was as expected (50%), but only 36% of females were successfully weaned (10/2017).
A targeting vector was designed to insert a single loxP site upstream of the promoter region of the granulin (Grn) gene. A second loxP site 3' to a FRT-flanked neomycin/kanamycin (neo/kan) resistance cassette was placed downstream of exon 4 . The construct was electroporated into C57BL/6-derived C2J embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts and chimeric mice were bred with mice expressing Cre-recombinase driven by chicken actin gene promoter (CAG-cre; predominately on a C57BL/6 background) to remove the neo/kan selection cassette. Mice lacking both the intact Grn gene and the CAG-cre transgene were backcrossed to C57BL/6 for at least five generations to establish a colony of (Grn-/-). Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation.
|Allele Name||targeted mutation 1.1, Aihao Ding|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Grn, granulin|
|Strain of Origin||B6(Cg)-Tyrc-2J/J|
|Molecular Note||Cre mediated recombination removed exons 1 through 4. The absence of protein expression was confirmed by western blot analysis on bone marrow-derived macrophages.|
|Mutations Made By|| |
Aihao Ding, Weill Medical School of Cornell University
Although homozygotes are reported to be viable and fertile, significant pre-wean loss of females is observed in The Jackson Laboratory homozygous breeding colony. Of 285 pups born over 8 months, the percentage of males weaned was as expected (50%), but only 36% of females were successfully weaned indicative of a high rate of pre-wean female mortality for this strain. (10/2017).
When using the PGRN KO mouse strain in a publication, please cite the originating article(s) and include JAX stock #013175 in your Materials and Methods section.
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