Mice homozygous for the LRRK2 R1441C knockin (R1441C KI) express the R1441C mutant form of leucine-rich repeat kinase 2 (Lrrk2) associated with Parkinson's disease. These LRRK2 R1441C KI mice may be useful in studying abnormal regulation of activity-dependent dopamine neurotransmission and D2 receptor-mediated function, which may represent pathogenic precursors preceding dopaminergic degeneration in Parkinson's disease.
Jie Shen, Harvard Med Sch/Brigham Women's HospRead More +
Mice homozygous for the LRRK2 R1441C knockin (R1441C KI) allele are viable and fertile, with expression of the R1441C mutant form of leucine-rich repeat kinase 2 (Lrrk2) associated with Parkinson's disease. Homozygous LRRK2 R1441C KI mice appear grossly normal and exhibit no spontaneous dopaminergic neurodegeneration or alterations in steady-state levels of striatal dopamine up to two years of age. Homozygous mice have significantly impaired dopaminergic transmission and impaired dopamine D2 receptor-mediated function. Specifically, homozygotes show reduced psychostimulant (amphetamine)-induced locomotor activity and reduced sensitivity to D2 receptor agonist (quinpirole)-induced locomotor inhibition. Also, nigral neurons from homozygous acute horizontal midbrain slices exhibit decreased sensitivity to inhibition of firing induced by dopamine, quinpirole, and amphetamine. Chromaffin cells cultured from homozygous mice also show compromised potassium-stimulated exocytotic catecholamine release.
A targeting vector was designed to insert the Parkinson's disease-associated R1441C missense mutation into the highly conserved GTPase domain in exon 31 (as well as a loxP-flanked PGK-neo cassette downstream of exon 31) of the Lrrk2 (leucine-rich repeat kinase 2) locus. This construct was electroporated into (C57BL/6 x 129)F1-derived MKV6.5 embryonic stem (ES) cells. Correctly targeted ES cells were then transiently transfected with a Cre recombinase-expressing plasmid to remove the PGK-neo cassette. The resulting ES cells with the LRRK2 R1441C knockin (and a single loxP site downstream of exon 31) were injected into recipient blastocysts. Chimeric mice were bred with B6/129 F1 mice to generate the mutant colony. Heterozygous mice were bred together for many generations prior to arrival at The Jackson Laboratory. Upon arrival, mice were bred with B6129SF1/J hybrid mice (Stock No. 101043) for at least one generation to establish the colony.
|Allele Name||targeted mutation 1.1, Jie Shen|
|Gene Symbol and Name||Lrrk2, leucine-rich repeat kinase 2|
|Gene Synonym(s)||4921513O20Rik; 4921513O20Rik; 9330188B09Rik; 9330188B09Rik; AURA17; AW561911; D630001M17Rik; D630001M17Rik; DARDARIN; Gm927; LOC381026; PARK8; RIKEN cDNA 4921513O20 gene; RIKEN cDNA 9330188B09 gene; RIKEN cDNA D630001M17 gene; RIPK7; ROCO2; cDNA sequence, clone 3-75; cI-46; gene model 927, (NCBI)|
|Promoter||Lrrk2, leucine-rich repeat kinase 2, mouse, laboratory|
|Strain of Origin||(C57BL/6 x 129)F1|
|Molecular Note||Exon 31 was replaced with one in which nucleotide substitutions led to the amino acid substitution of cysteine for arginine at position 1441 (R1441C). A floxed neo cassette was inserted downstream of the modified exon and removed by transient cre expression in ES cells.|
|Mutations Made By|| |
Jie Shen, Harvard Med Sch/Brigham Women's Hosp
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