LRRK2 KO1 mice have the promoter and exon 1 of the Lrrk2 gene deleted. These mice may be useful in studying the cellular function of LRRK2 during aging in the maintenance of protein homeostasis.
Jie Shen, Harvard Med Sch/Brigham Women's Hosp
Genetic Background | Generation |
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Allele Type | Gene Symbol | Gene Name |
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Targeted (Null/Knockout) | Lrrk2 | leucine-rich repeat kinase 2 |
Mice homozygous for the LRRK2 KO1 mutation are viable and fertile, with the promoter and exon 1 of the Lrrk2 (leucine-rich repeat kinase 2) gene deleted. No mRNA or protein expression from the targeted allele is observed in brain tissues, however a truncated mRNA signal is observed in kidney tissue. Homozygous mice do not exhibit neurodegeneration or neuropathological changes in the brain. In the kidneys, a tissue where LRRK2 is normally expressed at ~6-fold greater levels than brain, homozygous loss of LRRK2 results in renal atrophy by 20 months of age. This is accompanied by significant (~60-fold) age-dependent accumulation of aggregated α-synuclein and ubiquitinated proteins in the kidney. Specifically, homozygous KO kidneys show widely distributed cytosolic α-synuclein-immunoreactive granular aggregates (some amy also contain phospho-Ser-129 α-synuclein) or inclusions in boxy cells of renal tubules in the cortical area by 20 months of age. Other kidney defects observed in homozygous mice include impaired ubiquitin-proteasome system(UPS)-mediated protein degradation, impaired autophagy-lysosomal pathway, increased apoptotic cell death, inflammatory response, and oxidative damage. When combined with a null allele of Lrrk1, it has been reported that double homozygotes exhibit age-dependent loss of dopaminergic neurons and an impairment of the autophagy-lysosomal pathway. These LRRK2 KO1 mice may be useful in studying the cellular function of LRRK2 during aging in the maintenance of protein homeostasis.
A targeting vector was designed to replace the region encompassing the promoter and exon 1 of the Lrrk2 (leucine-rich repeat kinase 2) locus with a loxP-flanked PGK-neo cassette. This construct was electroporated into (C57BL/6 x 129)F1-derived MKV6.5 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. Chimeric mice were bred with B6/129 F1 mice to generate the mutant colony. Next, the mutant mice were bred with CaMKII-Cre transgenic mice on a B6 background. Offspring with the floxed PGK-neo cassette deleted in the germline were bred together (and the CaMKII-Cre transgene was selectively removed) for many generations. Upon arrival at The Jackson Laboratory Repository, mice were bred with B6129SF1/J hybrid mice (Stock No. 101043) for at least one generation to establish the colony.
Allele Name | targeted mutation 2.1, Jie Shen |
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Allele Type | Targeted (Null/Knockout) |
Allele Synonym(s) | Lrrk2KO1 |
Gene Symbol and Name | Lrrk2, leucine-rich repeat kinase 2 |
Gene Synonym(s) | |
Strain of Origin | (C57BL/6 x 129)F1 |
Chromosome | 15 |
Molecular Note | The promoter region and exon 1 were replaced with a floxed neo cassette. Cre mediated recombination removed the neo cassette. The absence of protein expression was confirmed by western blot analysis on brain extracts. |
Mutations Made By | Jie Shen, Harvard Med Sch/Brigham Women's Hosp |
When maintaining a live colony, homozygous mice may be bred together.
When using the B6;129-Lrrk2tm2.1Shn/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #016209 in your Materials and Methods section.
Facility Barrier Level Descriptions
Service/Product | Description | Price |
---|---|---|
Heterozygous for Lrrk2<tm2.1Shn> |
Frozen Mouse Embryo | B6;129-Lrrk2<tm2.1Shn>/J | $2595.00 |
Frozen Mouse Embryo | B6;129-Lrrk2<tm2.1Shn>/J | $2595.00 |
Frozen Mouse Embryo | B6;129-Lrrk2<tm2.1Shn>/J | $3373.50 |
Frozen Mouse Embryo | B6;129-Lrrk2<tm2.1Shn>/J | $3373.50 |
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