Overview

Hypocretin (orexin) containing neurons are ablated in these transgenic mice, which may be useful in studies of narcolepsy, regulation of sleep/wakefulness, feeding behavior, and metabolic homeostasis.

Donating Investigator

Thomas Scammell, Beth Israel Deaconess Medical Center

Genetic overview

Genetic Background	Generation

Tg(HCRT-MJD)1Stak

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

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Research Applications

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Base Price

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$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

These transgenic mice express a human ATXN3, ataxin 3, gene (a cDNA fragment encoding amino acid 286 to the C terminus, with 77 polyglutamine repeats, obtained from a patient with Machado-Joseph disease), under the control of the human HCRT, hypocretin (orexin) neuropeptide precursor, 3.2 kb upstream region, promoter. In transgenic mice, approximately 12 weeks of age, transgene expression results in the ablation of hypocretin (orexin) neurons (>99% loss). By 2 weeks of age, transgenic mice exhibit a loss of approximately half of hypocretin (orexin) containing neurons. Transgenic mice display reduced stress-induced hyperthermia, hypoactivity, and lower basal arterial blood pressure than wildtype controls. At approximately 6 weeks of age, transgenic mice display narcoleptic episodes consisting of a sudden stop to motor activity, postural changes, and ending with complete resumption of motor activity.
While transgenic mice exhibit a level of sensitivity to anesthesia (induction of anesthesia) that is similar to wildtype controls, mutant mice have a delayed emergence from anesthesia (50% more time to emerge for both isoflurane and sevoflurane). No cataplectic episodes were detected during anesthesia experiments. Transgenic mice exhibit shorter retention of social recognition when compared to wildtype controls. Hippocampal synaptic plasticity is altered with both paired pulse facilitation (PPF) and long-term potentiation (LTP) are attenuated. Mice that are hemizygous for the targeted mutation are viable and fertile. The Donating Investigator has not attempted to make the strain homozygous.

Development

A transgenic insert designed by Dr. Takeshi Sakurai (University of Tsukuba) containing a human ATXN3, ataxin 3, gene (a cDNA fragment encoding amino acid 286 to the C terminus, with 77 polyglutamine repeats, obtained from a patient with Machado-Joseph disease), under the control of the 3.2 kb upstream region of the human HCRT, hypocretin (orexin) neuropeptide precursor, promoter, as well as a 5' HA epitope, 3' myc-tag, and a mouse protamine 1 (mP1) intron and poly(A) signal. The transgenic insert was injected into fertilized (C57BL/6 x DBA/1)F1 mouse eggs. Founder line 1 was subsequently established. The mice were then backcrossed to C57BL/6 for 15 generations by the Donating Investigator, Dr. Thomas Scammell (Beth Israel Deaconess Medical Center). The Donating Investigator has not attempted to make the strain homozygous. Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J (Stock No. 000664) at least once to establish the colony.

Expression Data

Expressed Gene	ATXN3, ataxin 3, human
Site of Expression

Control Suggestions

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Zhang W; Sakurai T; Fukuda Y; Kuwaki T. 2006. Orexin neuron-mediated skeletal muscle vasodilation and shift of baroreflex during defense response in mice. Am J Physiol Regul Integr Comp Physiol 290(6):R1654-63PubMed: 16410401 MGI: J:201120
Hara J; Beuckmann CT; Nambu T; Willie JT; Chemelli RM; Sinton CM; Sugiyama F; Yagami K; Goto K; Yanagisawa M; Sakurai T. 2001. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30(2):345-54PubMed: 11394998 MGI: J:69620

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Genetics

Tg(HCRT-MJD)1Stak

Allele Symbol: Tg(HCRT-MJD)1Stak

Allele Name	transgene insertion 1, Takeshi Sakurai
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	Tg(HCRT-MJD)1Stak; transgene insertion 1, Takeshi Sakurai
Gene Symbol and Name	Tg(HCRT-MJD)1Stak, transgene insertion 1, Takeshi Sakurai
Gene Synonym(s)	orexin/ataxin-3; ORX/ATX-Tg
Promoter	HCRT, hypocretin neuropeptide precursor, human
Expressed Gene	ATXN3, ataxin 3, human
Strain of Origin	(C57BL/6 x DBA/1)F1
Chromosome	UN
Molecular Note	The transgenic construct contained a carboxy terminal MJD cDNA fragment derived from a patient with Machado-Joseph disease adjoined to a human HCRT promoter. The promoter region consisted of 3.2 kb of 5' upstream region in addition to the the noncoding exon 1. Expression was directed specifically in hypocretin neurons. The MJD fragment contained 77 polyglutamine repeats and was tagged with a Myc epitope tag for histological examination. Expression of the MJD fragment resulted in the ablation of hypocretin containing neurons

Disease/Phenotype

Disease Terms

Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

narcolepsy

Research Areas By Genotype

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

Mammalian Phenotype Terms by Genotype

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

Genotype: Tg(HCRT-MJD)1Stak/?
involves: C57BL/6 * DBA/1

behavior/neurological phenotype

abnormal circadian feeding behavior
- during the dark phase, mice consume 30% less food than wild-type mice

abnormal sleep pattern
- during the light period, mice exhibit shorter REM sleep and wake episodes compared to wild-type mice
- mice exhibit a decrease in the intervals between successive REM sleep periods and shorter latency to REM sleep compared to wild-type mice
- mice exhibit direct transitions from wake to REM unlike wild-type mice

decreased food intake
- during the dark phase, mice consume 30% less food than wild-type mice

fragmentation of sleep/wake states
- mice show severe sleep/wake fragmentation

hypoactivity
- during the dark period

narcolepsy
- beginning at 6 weeks of age, mice exhibit narcoleptic episodes with abrupt cessation of purposeful motor activity in which a sustained posture change is held until motion is abruptly resumed
- narcoleptic episodes occur during grooming or excited ambulation, last a few seconds to 150 seconds, and are often followed by increased feeding and drinking behaviors

growth/size/body region phenotype

increased susceptibility to age related obesity
- at 10 to 12 weeks of age, mice exhibit increased body weight compared to wild-type mice
- female but not male mice over 100 days in age have significant increases in body weight compared to littermate controls

homeostasis/metabolism phenotype

decreased energy expenditure

increased circulating leptin level
- 53% increase in the circulating leptin levels to bodyweight ratio in female but not male mice

nervous system phenotype

neuron degeneration
- by 2 and 12 weeks of age 56% and 99%, respectively, of orexin-containing neurons are lost

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

Genotype: Tg(HCRT-MJD)1Stak/?
B6.Cg-Tg(HCRT-MJD)1Stak

behavior/neurological phenotype

abnormal circadian feeding behavior
- at night, mice consume less food than wild-type mice due to reduced duration of wake time

abnormal drinking behavior
- at night, mice consume less water than wild-type mice due to reduced duration of wake time
- initially, upon waking, mice consume more water than wild-type mice

abnormal sleep pattern
- mice exhibit more frequent short and fewer long episodes of wake and non-rapid eye movement (NREM) sleep compared to wild-type mice
- mice exhibit more REM sleep than wild-type mice during the night and direct transition from wake to REM sleep (DREM) unlike wild-type mice
- mice exhibit shorter transition from NREM to REM and more episodes of REM at night than wild-type mice

decreased exploration in new environment
- mice fail to exhibit as substantial of an increase in locomotor activity during dark phase as in wild-type mice when exposed to a novel environment

hypoactivity
- at night, mice exhibit decreased activity compared to wild-type mice due to reduced duration of wake time

narcolepsy

growth/size/body region phenotype

increased susceptibility to age related obesity
- female but not male mice over 150 days in age have significant increases in body weight compared to littermate controls
- Background Sensitivity - the increase is not as great as found in mice with the same transgene on a mixed (C57BL/6 and DBA/1) background

homeostasis/metabolism phenotype

abnormal body temperature
- body temperature is higher than in wild-type between ZT14 and ZT18 and lower between ZT22 and ZT4 likely due to larger sleep-state dependent fluctuations in body temperature compared to in wild-type mice

decreased energy expenditure
- especially during the day

nervous system phenotype

abnormal brain wave pattern
- mice exhibit a higher electroencephalogram power densities at the theta and beta band during DREM than in wild-type mice indicating a cataplexy-like state

References

Zhang W; Sakurai T; Fukuda Y; Kuwaki T. 2006. Orexin neuron-mediated skeletal muscle vasodilation and shift of baroreflex during defense response in mice. Am J Physiol Regul Integr Comp Physiol 290(6):R1654-63PubMed: 16410401 MGI: J:201120
Hara J; Beuckmann CT; Nambu T; Willie JT; Chemelli RM; Sinton CM; Sugiyama F; Yagami K; Goto K; Yanagisawa M; Sakurai T. 2001. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30(2):345-54PubMed: 11394998 MGI: J:69620

Additional - Tg(HCRT-MJD)1Stak related

Technical Support

Contact Technical Support

Genotyping Protocols
- High Resolution Melting: Tg(HCRT-MJD)1Stak
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, hemizygous mice may be bred together, to wildtype siblings, or to C57BL/6J inbred mice (Stock No. 000664). The Donating Investigator has not attempted to make the strain homozygous.
- Additional Breeding and Husbandry Support
Citation
When using the B6.Cg-Tg(HCRT-MJD)1Stak/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #023418 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
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Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service	Genotype	Price
	Hemizygous or Non carrier for Tg(HCRT-MJD)1Stak

We will fulfill your order by providing at least two carriers for each strain ordered. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided. Please check genotypes which will be recovered. While the genotypes of all animals produced will be communicated to you prior to scheduling shipment, the genotypes of animals provided may not reflect the mating scheme and genotypes described in the strain description. Animals are typically ready to ship in 11-14 weeks. If a second recovery is required to produce the minimum number of animals, then delivery time would increase to approximately 25 weeks. If we fail to produce animals of the correct genotype, you will not be charged. We 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.

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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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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Tg(HCRT-MJD)1Stak

Allele Symbol: Tg(HCRT-MJD)1Stak

Disease Terms

Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

Research Areas By Genotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Tg(HCRT-MJD)1Stak/?involves: C57BL/6 * DBA/1

behavior/neurological phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

nervous system phenotype

Genotype: Tg(HCRT-MJD)1Stak/?B6.Cg-Tg(HCRT-MJD)1Stak

behavior/neurological phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

nervous system phenotype

References

Additional - Tg(HCRT-MJD)1Stak 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

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Genotype: Tg(HCRT-MJD)1Stak/?
involves: C57BL/6 * DBA/1

Genotype: Tg(HCRT-MJD)1Stak/?
B6.Cg-Tg(HCRT-MJD)1Stak