Strain Name:

B6;129-Lrrk2tm1.1Shn/J

Stock Number:

009347

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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.

Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Mutant Stock; Targeted Mutation;
Additional information on Genetically Engineered and Mutant Mice.
Visit our online Nomenclature tutorial.
Specieslaboratory mouse
GenerationF?pN1
Generation Definitions
 
Donating Investigator Jie Shen,   Harvard Med Sch/Brigham Women's Hosp

Description
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.

Development
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.

Control Information

  Control
   101043 B6129SF1/J (approximate)
 
  Considerations for Choosing Controls

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Parkinson's Disease Models
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003190   B6.129S2-Drd2tm1Low/J
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017946   B6.129S4-Pink1tm1Shn/J
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013583   B6.Cg-Tg(tetO-LRRK2)C7874Cai/J
000544   B6.D2-Cacna1atg/J
012445   B6.FVB-Tg(LRRK2)WT1Mjfa/J
012446   B6.FVB-Tg(LRRK2*G2019S)1Mjfa/J
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009688   B6;129-Dbhtm2(Th)Rpa Thtm1Rpa/J
008883   B6;129-Gt(ROSA)26Sortm1(SNCA*A53T)Djmo/TmdJ
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008886   B6;129-Gt(ROSA)26Sortm3(SNCA*E46K)Djmo/TmdJ
016209   B6;129-Lrrk2tm2.1Shn/J
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013050   B6;129-Pink1tm1Aub/J
004807   B6;129-Psen1tm1Mpm Tg(APPSwe,tauP301L)1Lfa/Mmjax
006390   B6;129-Sncatm1Sud Sncbtm1.1Sud/J
008532   B6;129-Thtm1(cre/Esr1)Nat/J
008333   B6;129P2-Dldtm1Ptl/J
008333   B6;129P2-Dldtm1Ptl/J
002596   B6;129P2-Nos2tm1Lau/J
003243   B6;129S-Tnfrsf1atm1Imx Tnfrsf1btm1Imx/J
003692   B6;129X1-Sncatm1Rosl/J
016575   B6;C3-Tg(PDGFB-LRRK2*G2019S)340Djmo/J
016576   B6;C3-Tg(PDGFB-LRRK2*R1441C)574Djmo/J
008169   B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J
004479   B6;C3-Tg(Prnp-SNCA*A53T)83Vle/J
000231   B6;C3Fe a/a-Csf1op/J
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018768   B6N.Cg-Tg(SNCA*E46K)3Elan/J
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018785   C57BL/6J-Tg(LRRK2*G2019S)2AMjff/J
018786   C57BL/6J-Tg(LRRK2*R1441G)3IMjff/J
008245   C57BL/6J-Tg(Th-SNCA)5Eric/J
008239   C57BL/6J-Tg(Th-SNCA*A30P*A53T)39Eric/J
016122   C57BL/6N-Lrrk1tm1.1Mjff Lrrk2tm1.1Mjff/J
016121   C57BL/6N-Lrrk2tm1.1Mjff/J
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View Parkinson's Disease Models     (112 strains)

Strains carrying   Lrrk2tm1.1Shn allele
009346   B6.Cg-Lrrk2tm1.1Shn/J
View Strains carrying   Lrrk2tm1.1Shn     (1 strain)

View Strains carrying other alleles of Lrrk2     (10 strains)

Additional Web Information

Visit the Parkinson's Disease Resource site for helpful information on Parkinson's and research resources.

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI
- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested.
Parkinson Disease 8, Autosomal Dominant; PARK8   (LRRK2)
View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

Lrrk2tm1.1Shn/Lrrk2tm1.1Shn

        involves: 129 * C57BL/6
  • nervous system phenotype
  • *normal* nervous system phenotype
    • mice exhibit normal dopaminergic neurons and striatal catecholamine levels   (MGI Ref ID J:151944)
    • abnormal action potential
      • the response of nigral neurons to dopamine treatment exhibits a smaller amplitude and shorter duration of hyperpolarization than in similarly treated wild-type cells   (MGI Ref ID J:151944)
      • dopamine-treated nigral neurons exhibit a shorter time to predrug firing activity compared with similarly treated wild-type neurons   (MGI Ref ID J:151944)
      • quinpirole-treated nigral neurons are less sensitive than similarly treated wild-type neurons   (MGI Ref ID J:151944)
      • amphetamine-treated neurons exhibit a shorter cessation of firing compared with similarly treated wild-type neurons with smaller hyperpolarization   (MGI Ref ID J:151944)
  • homeostasis/metabolism phenotype
  • abnormal response/metabolism to endogenous compounds
    • the response of nigral neurons to dopamine treatment exhibits a smaller amplitude and shorter duration of hyperpolarization than in similarly treated wild-type cells   (MGI Ref ID J:151944)
    • dopamine-treated nigral neurons exhibit a shorter time to predrug firing activity compared with similarly treated wild-type neurons   (MGI Ref ID J:151944)
  • decreased physiological sensitivity to xenobiotic
    • amphetamine-treated neurons exhibit a shorter cessation of firing compared with similarly treated wild-type neurons with smaller hyperpolarization   (MGI Ref ID J:151944)
  • behavior/neurological phenotype
  • impaired behavioral response to xenobiotic
    • following treatment with amphetamine, mice fail to exhibit an increase in locomotor activity unlike similarly treated wild-type mice   (MGI Ref ID J:151944)
    • mice treated with quinpirole do not exhibit as much of a decrease in locomotor activity (horizontal and vertical movements) as similarly treated wild-type mice   (MGI Ref ID J:151944)
    • quinpirole-treated nigral neurons are less sensitive than similarly treated wild-type neurons   (MGI Ref ID J:151944)
    • impaired behavioral response to addictive substance
      • following treatment with amphetamine, mice fail to exhibit an increase in locomotor activity unlike similarly treated wild-type mice   (MGI Ref ID J:151944)
  • endocrine/exocrine gland phenotype
  • abnormal adrenal gland secretion
    • adrenal chromaffin cells exhibit reduced catecholamine release per cell, quantal size, and frequency of release events when stimulated with high potassium ion compared to similarly treated wild-type cells   (MGI Ref ID J:151944)
View Research Applications

Research Applications
This mouse can be used to support research in many areas including:

Neurobiology Research
Ataxia (Movement) Defects
Neurodegeneration
Parkinson's Disease
      LRRK2 strains
Receptor Defects
      dopamine receptor

Research Tools
Neurobiology Research

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Lrrk2tm1.1Shn
Allele Name targeted mutation 1.1, Jie Shen
Allele Type Targeted
Common Name(s) Lrrk2R1441C;
Mutation Made By Jie Shen,   Harvard Med Sch/Brigham Women's Hosp
Strain of Origin(C57BL/6 x 129)F1
Promoter Lrrk2, leucine-rich repeat kinase 2, mouse, laboratory
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. [MGI Ref ID J:151944]

Genotyping

Genotyping Information


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Tong Y; Pisani A; Martella G; Karouani M; Yamaguchi H; Pothos EN; Shen J. 2009. R1441C mutation in LRRK2 impairs dopaminergic neurotransmission in mice. Proc Natl Acad Sci U S A 106(34):14622-7. [PubMed: 19667187]  [MGI Ref ID J:151944]

Additional References

Lrrk2tm1.1Shn related

Parisiadou L; Yu J; Sgobio C; Xie C; Liu G; Sun L; Gu XL; Lin X; Crowley NA; Lovinger DM; Cai H. 2014. LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity. Nat Neurosci 17(3):367-76. [PubMed: 24464040]  [MGI Ref ID J:206832]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, homozygous mice may be bred together.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls


Pricing for USA, Canada and Mexico shipping destinations View International Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $2525.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryorecovery - Standard.
    Progeny testing is not required.

    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

Pricing for International shipping destinations View USA Canada and Mexico Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $3283.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryorecovery - Standard.
    Progeny testing is not required.

    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

View USA Canada and Mexico Pricing View International Pricing

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Control Information

  Control
   101043 B6129SF1/J (approximate)
 
  Considerations for Choosing Controls
  Control Pricing Information for Genetically Engineered Mutant Strains.
 

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.
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