B6.Cg-Tg(HCRT-MJD)1Stak/J

Stock number: 023418

Description

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.

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.

Allele

Symbol: Tg(HCRT-MJD)1Stak
Name: transgene insertion 1, Takeshi Sakurai
MGI accession ID: MGI:2387763
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Tg(HCRT-MJD)1Stak
Marker name: transgene insertion 1, Takeshi Sakurai
Chromosome: UN
Strain of origin: (C57BL/6 x DBA/1)F1
Expressed genes: ATXN3,ataxin 3,human
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