Strain Detail Sheet

Strain Name:
B6.129S1-Htttm8(HTT*)Szi/Mmjax
Stock Number:
069797-JAX
Citation ID:
RRID:MMRRC_069797-JAX
Other Names:
LacQ140

Strain Information

Gene Details

Htttm8(HTT*)Szi
Name: huntingtin; targeted mutation 8, Scott Zeitlin
Synonyms: Htt Q175, HttLacQ140
Type: Allele
Species: Mus musculus (mouse)
Chromosome: 5
Alteration at locus: Knock-In
Htt
Name: huntingtin
Synonyms: HD, IT15, C430023I11Rik, htt, Hdh, huntingtin
Type: Gene
Species: Mouse
Chromosome: 5
Alteration at locus: Knock-In
NCBI: 15194
HGNC: HGNC:4851
Homologene: 1593
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Genetic Alterations
HttLacQ140 knock-in mice express an inducible human huntingtin (HTT) exon 1 sequence containing a CAG140 expanded repeat flanked by two Lac operator sequences. When HttLacQ140 mice are combined with mice expressing an E. coli Lac repressor, mutant HTT expression can be induced or repressed by the administration or withdrawal of the lactose analog IPTG. This strain maybe useful for Huntington's disease (HD) research.
Genotype Determination
ES Cell Line
W9.5/W95 derived from 129S1/Sv-Oca2+ Tyr+ Kitl+

Strain Description

Phenotype
Huntington's disease (HD) is an autosomally dominant, fatal neurodegenerative disorder characterized by uncontrolled movements, psychiatric disturbances and cognitive impairment. HD is caused by an unstable trinucleotide (CAG) repeat expansion in the huntingtin gene (HTT; HD or Hdh).

HttLacQ140 knock-in mice express an inducible human HTT exon 1 sequence containing a CAG140 expanded repeat flanked by two Lac operator sequences. Mice heterozygous for the mutation are viable and fertile. The donating investigator has not tried to generate homozygotes. When the LacQ140 mouse is crossed with a transgenic mouse line globally expressing Lac repressor from the beta actin promoter, levels of mutant HTT expression in double mutant progeny can be controlled by the addition or withdrawal of the lactose analog, IPTG, to the mouse's drinking water. In the absence of IPTG administration, mutant HTT expression is repressed by 50% in heterozygous HttLacQ140 mice. In the presence of IPTG, the mutant HTT allele is expressed at normal levels. When mutant HTT expression is repressed early (at ages up to 6 months of age), formation of mHTT protein striatal neuronal intranuclear inclusion bodies is delayed, behavioral (as determined by the SmartCube, NeuroCube and PhenoCube platforms), motor, and transcriptional dysregulation is ameliorated, and the increase in neurofilament light chain levels in cerebrospinal fluid is delayed, however the improvements are diminished by 12 months of age. If mutant HTT expression is repressed after 6 months of age, the benefit of mutant HTT lowering is reduced. Regardless of when mHTT expression is reduced, the benefits of HTT lowering are diminished in older mice (12 months of age and older).

In these mutant mice, the CAG repeat number is subject to germline and somatic instability, and may expand or contract. When using lines with unstable CAG repeat length, it is strongly recommended the CAG repeat number be quantified in all the experimental animals; all animals in all experimental groups should carry comparable CAG repeat sizes. CAG repeat sizing of HD mice should be done using high-resolution methods; as assays based on agarose gel electrophoresis typically do not provide sufficient resolution to accurately measure CAG repeat numbers. If labs do not have access to the appropriate equipment for determining CAG repeat length, CAG repeats can be evaluated on a fee-for-service basis by Laragen, Inc. This strain is maintained with between 140-160 CAG repeats.
MeSH Terms
  • Mice
  • Humans
  • Animals
  • Infant
  • Huntington Disease/drug therapy
  • Huntington Disease/genetics
  • Protein Aggregates
  • Huntingtin Protein/genetics
  • Huntingtin Protein/cerebrospinal fluid
  • Disease Models, Animal
  • Corpus Striatum/metabolism
  • Disease Progression
Strain Development
The HttLacQ140 targeting vector was designed to insert a cassette containing synthetic LacO sequences flanking the Htt transcriptional start site followed by a chimeric mouse/human Htt/HTT sequence with human exon 1 into the mouse Htt locus on chromosome 5. The human sequence encodes the N terminal sequence including an expanded CAG repeat containing 140Q and the adjacent sequence encoding the human proline-rich region. A loxP-flanked PGK-neomycin cassette was inserted in reverse orientation 1.3 kb upstream of transcription initiation site. The construct was electroporated into 129S1/Sv-derived W9.5 embryonic stem (ES) cells and correctly targeted ES cells were injected into blastocysts. The resulting chimeras were bred with C57BL/6J mice and backcrossed using the speed congenic approach. Mice have a sequenced CAG repeat length of 155+/- 3.3. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).
Suggested Control Mice
C57BL/6J

MMRRC Genetic QC

MMRRC Genetic QC Summary
The MMRRC Centers have developed a genetic QC pipeline using MiniMUGA array genotyping to provide additional information on strain backgrounds for MMRRC congenic and inbred strains. For more information on when data may be available, or to request genotyping for a strain of interest, please contact csmmrrc@jax.org. Older strains may not have this information.

Research Applications

  • Models for Human Disease

Strain Origin

Donor
Scott Zeitlin, Ph.D., University of Virginia.
Primary Reference

Marchionini DM, Liu JP, Ambesi-Impiombato A, Kerker K, Cirillo K, Bansal M, Mushlin R, Brunner D, Ramboz S, Kwan M, Kuhlbrodt K, Tillack K, Peters F, Rauhala L, Obenauer J, Greene JR, Hartl C, Khetarpal V, Lager B, Rosinski J, Aaronson J, Alam M, Signer E, Muñoz-Sanjuán I, Howland D, Zeitlin SO. Benefits of global mutant huntingtin lowering diminish over time in a Huntington's disease mouse model. JCI Insight. 2022 Oct 24;7(20):e161769. doi: 10.1172/jci.insight.161769. (Medline PMID: 36278490)

Colony and Husbandry Information

Special Considerations

To de-repress the LacQ140 allele, IPTG is added to the drinking water (10 mM) or food chow (2.5 g/kg). IPTG water should be changed every 3-4 days, and the water should be protected from light.

Health Status Report

For more information about this colony's health status contact csmmrrc@jax.org

Appearance

Coat Color
Black
Eye
Black

Breeding

MMRRC Breeding System
Backcross
Generation
N>10 in the C57BL/6J genetic background
Overall Breeding Performance
Excellent

Reproductive Statistics

Viability and Fertility: Female Male Comments
Homozygotes are viable: Yes Yes
Homozygotes are fertile: Yes Yes
Heterozygotes are fertile: Yes Yes
Age Reproductive Decline: 4 to 6 months 4 to 6 months
Average litter size
4 to 6
Recommended wean age
3 Weeks
Average Pups Weaned
4 to 6

Order Request Information

Availability Level

Limited quantities of breeder mice (up to 2 males and 2 females or 4 mice) per investigator per month are available from a live colony, usually available to ship in under 12 weeks. Larger quantities may be available, please contact the distributing center directly at csmmrrc@jax.org for more details.

Cryopreserved material may be available upon request, please inquire to csmmrrc@jax.org for more information.

Conditions of Distribution

Distribution of this strain requires submission of the MMRRC Conditions of Use (COU). A link to the COU web form will be provided via email after an order has been placed; the form should be completed then or the email forwarded to your institutional official for completion.

Fees

Additional charges may apply for any special requests. Shipping costs are in addition to the basic distribution/resuscitation fees. Information on shipping costs and any additional charges will be provided by the supplying MMRRC facility.

Click button to Request this one strain. (Use the MMRRC Catalog Search to request more than one strain.)
MMRRC Item # Description Distribution Fee / Unit (US $)
*Shipping & Handling not included*		 Units Notes
069797-JAX-HET-F
069797-JAX-HET-M
069797-JAX-WT-F
069797-JAX-WT-M
Heterozygous / Hemizygous Female
Heterozygous / Hemizygous Male
Wild Type Female
Wild Type Male
 $218.00 / $218.00
Non-Profit / For-Profit		 Per Mouse The csmmrrc@jax.org may assess additional fees for any special requests (e.g., specific age or weight of mice, etc.).
Cryopreserved material may be available upon request, please inquire to csmmrrc@jax.org for more information.

1 The distribution fee covers the expense of rederiving mice from a live mouse; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.

2 An aliquot contains a sufficient number of embryos (in one or more vials or straws and based on the transfer success rate of the MMRRC facility) to transfer into one to three recipients. The MMRRC makes no guarantee concerning embryo transfer success experienced in the recipient investigator's laboratory. Neither gender nor genotype ratios are guaranteed.

3 An aliquot is one straw or vial with sufficient sperm to recover at least one litter of mice, as per provided protocols, when performed at the MMRRC facility. The MMRRC makes no guarantee concerning the success of these procedures when performed outside the MMRRC facilities.

4 The distribution fee covers the expense of resuscitating mice from the cryo-archive; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.

To request material from the MMRRC: Please fill out our on-line request form (accessible from the catalog search results page, or click the Request this Strain button in the fees section). If you have questions or need assistance completing this form, you may call Customer Service at (800) 910-2291 (in USA or Canada) or (530) 757-5710 (international calls). Before you call, please have with you: the MMRRC item number, quantity needed, Bill-to and Ship-to contact information.