Overview

Dopamine-deficient (DA-deficient, DA^-/-, or DD) mice are homozygous for the TH mutant allele and heterozygous for the DBH-TH mutant allele (Th^-/-;Dbh^Th/+). While no expression from the TH mutant allele is observed in any tissues (resulting in deficiency of both dopamine (DA) and norepinephrine (NE)), the DBH-TH mutant allele contains the TH coding sequence under the control of the endogenous DBH promoter region and restores TH expression in noradrenergic neurons. These DD mice may be useful in studying dopaminergic neurobiology (including neurotransmitters, addiction, feeding, learning and memory, catecholamines, and Parkinsonian phenotypes).

Donating Investigator

Claire Cannon, Marquette University

Genetic overview

Genetic Background	Generation

Th^tm1Rpa

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Th	tyrosine hydroxylase

Dbh^tm2(Th)Rpa

Allele Type	Gene Symbol	Gene Name
Targeted	Dbh	dopamine beta hydroxylase

View Genetics

Research Applications

Neurobiology Research
Research Tools
Developmental Biology Research

View All Research Applications

Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Important Note

Dopamine-deficient (DA-deficient, DA^-/-, or DD) mice are homozygous for the TH mutant allele and heterozygous for the DBH-TH mutant allele (Th^-/-; Dbh^Th/+). When maintained as congenic on a C57BL/6 genetic background, Th^-/-; Dbh^Th/+ mice may exhibit declining birth rates and increased mortality (Hnasko et al 2007 J Neurosci 27:12484-8). Therefore, the colony at The Jackson Laboratory is maintained as heterozygous for both mutant alleles.

Detailed Description

Mice heterozygous for both targeted mutations are viable and fertile. Dopamine-deficient (DA-deficient, DA^-/-, or DD) mice are homozygous for the TH mutant allele and heterozygous for the DBH-TH mutant allele (Th^-/-; Dbh^Th/+). While no expression from the TH mutant allele is observed in any tissues (resulting in deficiency of both dopamine (DA) and norepinephrine (NE)), the DBH-TH mutant allele contains the TH coding sequence under the control of the endogenous DBH promoter region and restores TH expression in noradrenergic neurons. DD mice become hypoactive and hypophagic around two weeks of age and usually die before four weeks of age. Treatment with L-DOPA, the product of TH enzymatic activity, rescues size, feeding, and life span. These DD mice may be useful in studying dopaminergic neurobiology (including neurotransmitters, addiction, feeding, learning and memory, catecholamines, and Parkinsonian phenotypes).

NOTE: Th^-/-; Dbh^Th/+ mice congenic on a C57BL/6 genetic background may exhibit declining birth rates and increased mortality (Hnasko et al 2007 J Neurosci 27:12484-8).

Development

To generate the TH knockout allele , the pTH4 targeting vector was designed to replace the proximal promoter and first two exons of the Th locus with a PGK-neomycin resistance cassette. The construct was electroporated into 129S7/SvEvBrd-Hprt1⁺ derived AB1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts and the resulting heterozygous mice were maintained on a C57BL/6/129S hybrid background.

To generate the DBH-TH mutant allele (Dbh^Th), the pDBH-TH vector was designed to insert the entire mouse Th coding region (including 1 kb sequence after the polyA site) and a neo cassette between exons 1 and 2 of the Dbh locus. The construct was electroporated into unspecified embryonic stem (ES) cells and heterozygous animals were obtained.

Next, mice heterozygous for the TH mutant allele (Th^-/+) were bred with mice heterozygous for the DBH-TH mutant allele (Dbh^Th/+). The donating investigator reports that double mutant mice were subsequently backcrossed to C57BL/6J mice for several (9-14) generations prior to arrival at The Jackson Laboratory. Upon arrival, mutant mice were bred with C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.

A 27 SNP (single nucleotide polymorphism) panel analysis performed by The Jackson Laboratory revealed the mice to be ~85% C57BL/6 genetic background; 4 of 27 markers were segregating for C57BL/6 or 129S allele-type markers (on chromosomes 2, 3, 8 and 11). These data suggest that, prior to arrival at the Jackson Laboratory, the mice were not backcrossed to C57BL/6 for as many generations as originally reported.

Expression Data

Expressed Gene	Th, tyrosine hydroxylase, mouse, laboratory
Site of Expression

Control Suggestions

Approximate Controls

Additional Information

Considerations for Choosing Controls

Selected References

Cannon CM; Palmiter RD. 2003. Reward without dopamine. J Neurosci 23(34):10827-31PubMed: 14645475 MGI: J:86847
Hnasko TS; Sotak BN; Palmiter RD. 2007. Cocaine-conditioned place preference by dopamine-deficient mice is mediated by serotonin. J Neurosci 27(46):12484-8PubMed: 18003826 MGI: J:127594
Szczypka MS; Rainey MA; Kim DS; Alaynick WA; Marck BT; Matsumoto AM; Palmiter RD. 1999. Feeding behavior in dopamine-deficient mice. Proc Natl Acad Sci U S A 96(21):12138-43PubMed: 10518589 MGI: J:58125
Zhou QY; Palmiter RD. 1995. Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell 83(7):1197-209PubMed: 8548806 MGI: J:30404

View All References

Genetics

Th^tm1Rpa

Allele Symbol: Th^tm1Rpa

Allele Name	targeted mutation 1, Richard D Palmiter
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	DA-; pTH4; TH^-
Gene Symbol and Name	Th, tyrosine hydroxylase
Gene Synonym(s)
Strain of Origin	129S7/SvEvBrd-Hprt⁺
Chromosome	7
Molecular Note	A neomycin selection cassette replaced the proximal promoter and exons 1 and 2.

Dbh^tm2(Th)Rpa

Allele Symbol: Dbh^tm2(Th)Rpa

Allele Name	targeted mutation 2, Richard D Palmiter
Allele Type	Targeted
Allele Synonym(s)	Dbh^Th; DBH-TH^-
Gene Symbol and Name	Dbh, dopamine beta hydroxylase
Gene Synonym(s)
Expressed Gene	Th, tyrosine hydroxylase, mouse, laboratory
Strain of Origin	Not Specified
Chromosome	2
Molecular Note	The entire Th coding region, including 1kb sequence after the polyadenylation site and a neomycin resistance cassette, was inserted between exons 1 and 2 of the Dbh gene.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Neurobiology Research
- Response to Catecholamines
- Behavioral and Learning Defects
- Parkinson's Disease
- Neurotransmitter Receptor and Synaptic Vesicle Defects
Research Tools
- Toxicology Research
  - drug metabolism
  - drug/compound testing
Developmental Biology Research
- Perinatal Lethality

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Dbh^tm2(Th)Rpa/Dbh⁺ Th^tm1Rpa/Th^tm1Rpa
involves: 129S7/SvEvBrd

behavior/neurological phenotype

adipsia
- injection with L-DOPA restores drinking behavior

aphagia
- injection with L-DOPA restores eating behavior with maximal intake during the first 2 hours after injection and cessation of eating by about 6 hours post injection

decreased stereotypic behavior
- make about 280 stereotypical beam breaks per hour compared to about 700 per hour for controls

hunched posture
- at P10 - P15

hypoactivity
- at P10 - P15, travel only about 3m/hr compared to 23 m/hr in controls
- Normal - however at P16, reflexion, corneal, startle, righting, grasping, and placing reflexes are all similar to controls, balance is not impaired, and no tremors are seen
- within 15 minutes of injection of L-DOPA activity levels increase peaking at about 1 hour post injection and then decreasing so that by 12 hours post injection mice are hypoactive

poor grooming
- at P10 - P15

homeostasis/metabolism phenotype

decreased dopamine level
- dopamine levels in the brain are low; however, levels of norepinephrine in the brain, heart, salivary glands, and adrenal glands are similar to controls

mortality/aging

premature death
- all die by 4 weeks of age
- twice daily treatment with 50 mg/kg L-dihydroxyphenylalanine (L-DOPA) starting around P15 rescues the lethality

nervous system phenotype

abnormal nervous system physiology
- expression levels of tachykinin 1 and dynorphin are decreased in the striatum

decreased brain size
- brain size is reduced and neurons are slightly more compact; however, dopaminergic neuron and striatum morphology are similar to controls

growth/size/body region phenotype

decreased body size
- at P10 - P15

decreased body weight
- at P16, body weight is 70% of control littermates

weight loss
- after P17 a negative growth rate is seen
- twice daily treatment with 50 mg/kg L-DOPA starting around P15 restores a nearly normal growth rate

The following phenotype relates to a compound genotype created using this strain

Genotype: Dbh^tm2(Th)Rpa/Dbh⁺ Th^tm1Rpa/Th^tm1Rpa
involves: 129S7/SvEvBrd * C57BL/6J

behavior/neurological phenotype

abnormal gait
- 24 or more hours after L-DOPA treatment the gait is awkward

akinesia
- 24 hours after L-DOPA treatment 1- and 4-limb akinesia is increased compared to controls

catalepsy
- 24 hours after L-DOPA treatment forelimb catalepsy is increased compared to controls

decreased compensatory feeding amount
- after a 30 hour fast when presented with a high sucrose, high-fat diet mice begin to consume food but cease eating sooner and consume only about 25% of the amount eaten by wild-type mice
- if food is with held for 3 or 6 hours after L-DOPA treatment mice compensate by consuming more food in the next 3 hours to consume about the same amount of food as when food is continually available; however no compensation if food is with held for 9 hours
- s

decreased food intake
- during the first 24 hours after L-DOPA treatment food intake is similar to controls but during the next 24 hours intake decreases to about 10% of wild-type
- food intake is proportional to L-DOPA dose up to 100 mg/kg

hunched posture

hyperactivity
- for 6 - 9 hours after L-DOPA treatment activity level is higher than in wild-type
- treatment with L-DOPA and carbidopa induces a biphasic increase in activity that is more prolonged than when L-DOPA is given alone; however, in wild-type mice L-DOPA and carbidopa treatment induces inactivity

hypoactivity
- a second small peak of activity occurs between 24 and 40 hours after treatment however overall activity is decreased compared to controls
- in untreated mice or by 24 hours after L-DOPA treatment

hyporesponsive to tactile stimuli
- 1 hour after L-DOPA treatment a decrease in response in the paw pinch assay is seen

impaired behavioral response to addictive substance
- 19 hours after L-DOPA treatment a single dose of amphetamine (5mg/kg) induces a shorter increase in activity (1 hour compared to 2 hours in controls) and a second dose of amphetamine fails to alter activity unlike in controls

impaired coordination
- 24 or more hours after L-DOPA treatment rotarod and pole test performance are poor

increased stereotypic behavior
- treatment with L-DOPA and carbidopa induces intense stereotypic behavior (licking and chewing of paws) between 1 and 5 hours after treatment, no such behavior is seen in controls

integument phenotype

hyporesponsive to tactile stimuli
- 1 hour after L-DOPA treatment a decrease in response in the paw pinch assay is seen

mortality/aging

premature death
- can be maintained for at least 1.5 years with daily treatment of 50 mg/kg L-DOPA and feeding with breeder chow (4.35 kcal/g)

References

Cannon CM; Palmiter RD. 2003. Reward without dopamine. J Neurosci 23(34):10827-31PubMed: 14645475 MGI: J:86847
Hnasko TS; Sotak BN; Palmiter RD. 2007. Cocaine-conditioned place preference by dopamine-deficient mice is mediated by serotonin. J Neurosci 27(46):12484-8PubMed: 18003826 MGI: J:127594
Szczypka MS; Rainey MA; Kim DS; Alaynick WA; Marck BT; Matsumoto AM; Palmiter RD. 1999. Feeding behavior in dopamine-deficient mice. Proc Natl Acad Sci U S A 96(21):12138-43PubMed: 10518589 MGI: J:58125
Zhou QY; Palmiter RD. 1995. Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell 83(7):1197-209PubMed: 8548806 MGI: J:30404

Additional - Dbh^tm2(Th)Rpa related

Additional - Th^tm1Rpa related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Dbh STD PCR
- Standard PCR:Th STD PCR
- Standard PCR:Dbh MCA
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, mice heterozygous for both targeted alleles may be bred together. DD mice (homozygous for the TH mutant allele and heterozygous for the DBH-TH mutant allele; Th^-/-;Dbh^Th/+) become hypoactive and hypophagic around two weeks of age and usually die before 4 weeks of age. Further backcrossing to the C57BL/6 genetic background may result in declining birth rates and increased mortality of DD mice.
- Additional Breeding and Husbandry Support
Citation
When using the B6;129-Dbh^tm2(Th)Rpa Th^tm1Rpa/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #009688 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

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

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or Wild-Type for Dbh<tm2(Th)Rpa> , Heterozygous or Wild-Type for Th<tm1Rpa>

Related Products and Services

Frozen Mouse Embryo	B6;129-Dbh<tm2(Th)Rpa> Th<tm1Rpa>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	B6;129-Dbh<tm2(Th)Rpa> Th<tm1Rpa>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	B6;129-Dbh<tm2(Th)Rpa> Th<tm1Rpa>/J Frozen Embryo	$3373.50
Frozen Mouse Embryo	B6;129-Dbh<tm2(Th)Rpa> Th<tm1Rpa>/J Frozen Embryo	$3373.50

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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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Donating Investigator

Genetic overview

Research Applications

Base Price

Important Note

Detailed Description

Development

Expression Data

Control Suggestions

Approximate Controls

Additional Information

Selected References

Thtm1Rpa

Allele Symbol: Thtm1Rpa

Dbhtm2(Th)Rpa

Allele Symbol: Dbhtm2(Th)Rpa

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Dbhtm2(Th)Rpa/Dbh+ Thtm1Rpa/Thtm1Rpainvolves: 129S7/SvEvBrd

behavior/neurological phenotype

homeostasis/metabolism phenotype

mortality/aging

nervous system phenotype

growth/size/body region phenotype

Genotype: Dbhtm2(Th)Rpa/Dbh+ Thtm1Rpa/Thtm1Rpainvolves: 129S7/SvEvBrd * C57BL/6J

behavior/neurological phenotype

integument phenotype

mortality/aging

References

Additional - Dbhtm2(Th)Rpa related

Additional - Thtm1Rpa related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

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

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Th^tm1Rpa

Allele Symbol: Th^tm1Rpa

Dbh^tm2(Th)Rpa

Allele Symbol: Dbh^tm2(Th)Rpa

Genotype: Dbh^tm2(Th)Rpa/Dbh⁺ Th^tm1Rpa/Th^tm1Rpa
involves: 129S7/SvEvBrd

Genotype: Dbh^tm2(Th)Rpa/Dbh⁺ Th^tm1Rpa/Th^tm1Rpa
involves: 129S7/SvEvBrd * C57BL/6J

Additional - Dbh^tm2(Th)Rpa related

Additional - Th^tm1Rpa related