A floxed transcription-disrupter (TD) ablates expression of the mouse Hcrtr1 gene in this OX1R TD conditional mutant strain. Cre-mediated excision of the TD restores expression under the direction of the native promoter.
Thomas Scammell, Beth Israel Deaconess Medical Center
The Hcrtr1 (hypocretin (orexin) receptor 1; also called OX1R) gene plays a role in modulating reward and depression-like behavior. Orexin signaling has been implicated in processes as diverse as sleep-wake transitioning, the control of food intake, and autonomic output.
In this conditional mutant OX1R TD strain, a loxP-flanked transcription-disrupter (TD) cassette was introduced to intron 1 of the mouse Hcrtr1 gene to prevent expression of functional protein. Cre-mediated excision of the TD restores expression under the direction of the native promoter.
The impact of this mutation was first tested electrophysiologically using in vitro patch-clamp recordings of noradrenergic neurons of the locus coeruleus (LC), a type of neuron that expresses only OX1R but not OX2R. Orexin-A ligand depolarizes LC neurons from wildtype mice, but has no effect on LC neurons from homozygous OX1R TD mice. The deficit in LC neurons is fully restored after crossing OX1R TD mice with Zp3-Cre mice, which express Cre recombinase in the female germline.
Behaviorally, OX1R TD mice have a significant reduction in behavioral despair in the forced swim test and tail suspension test, but anxiety-like behavior is normal. These mice have normal wake, non-REM, and REM sleep behavior. Cataplexy (episodes of sudden muscle atonia during active wakefulness) does not occur in these mice. OX1/2R TD progeny from crosses with OX2R TD mice (see Stock No. 027707) have severely fragmented sleep/wake behavior, similar to that seen in prepro-orexin null mice.
OX1R TD mice are useful as OX1R null mice in their native state. More importantly, they can be used to study the effects of focal or global restoration of OX1R signaling, using methods that produce focal or germline expression of Cre recombinase, respectively. Focal OX1R restoration can be used to test whether OX1R signaling in a specific brain region is sufficient to rescue specific behaviors.
A floxed transcription disrupter cassette was inserted into intron 1 (formerly identified as intron 3) via homologous recombination in 129-derived embryonic stem (ES) cells. The TD cassette consists of a mouse En2 splice acceptor site followed by an SV40 enhancer, neomycin resistance gene, and two HSV-TK poly(A) signals (a synthetic poly(A) signal/transcriptional pause signal, and another synthetic poly(A) signal followed by a Myc-associated zinc finger protein-binding site). Resultant founder mice were backcrossed to C57BL/6J mice for more than 15 generations by the donating laboratory.
|Allele Name||targeted mutation 1, Michael M Scott|
|Allele Type||Targeted (Conditional ready (e.g. floxed), No functional change)|
|Allele Synonym(s)||targeted mutation 1, Michael M Scott; Hcrtr1tm1Mmsc|
|Gene Symbol and Name||Hcrtr1, hypocretin (orexin) receptor 1|
|Gene Synonym(s)||OX1R; Hctr1|
|Strain of Origin||129|
|Molecular Note||A floxed transcription disrupter cassette was inserted into intron 3 via homologous recombination. In situ hybridization analysis confirmed the absence of expression in the central nervous system of homozygous mice.|
Homozygotes and heterozygotes are viable and fertile.
When using the Hcrtr1 null mouse strain in a publication, please cite the originating article(s) and include JAX stock #027706 in your Materials and Methods section.
|Heterozygous or wild-type for Hcrtr1<tm1Mmsc>|
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.
"MICE" means mouse strains, their progeny derived by inbreeding or crossbreeding, unmodified derivatives from mouse strains or their progeny supplied by The Jackson Laboratory ("JACKSON"). "PRODUCT(S)" means biological materials supplied by JACKSON, and their derivatives. "SERVICES" means projects conducted by JACKSON for other parties that may include but are not limited to the use of MICE or PRODUCTS. "RECIPIENT" means each recipient of MICE, PRODUCTS, or SERVICES provided by JACKSON including each institution, its employees and other researchers under its control. MICE or PRODUCTS shall not be: (i) used for any purpose other than internal research, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services. Acceptance of MICE, PRODUCTS or SERVICES from JACKSON shall be deemed as agreement by RECIPIENT to these conditions, and departure from these conditions requires JACKSON’s prior written authorization.
MICE, PRODUCTS AND SERVICES ARE PROVIDED "AS IS". JACKSON EXTENDS NO WARRANTIES OF ANY KIND, EITHER EXPRESS, IMPLIED, OR STATUTORY, WITH RESPECT TO MICE, PRODUCTS OR SERVICES, INCLUDING ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, OR ANY WARRANTY OF NON-INFRINGEMENT OF ANY PATENT, TRADEMARK, OR OTHER INTELLECTUAL PROPERTY RIGHTS.
In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of, PRODUCTS or SERVICES, JACKSON will, at its option, provide credit or replacement for the PRODUCT received or the SERVICES provided; JACKSON makes no other representations and this shall be the exclusive remedy of the purchaser. Please note specific policy for live mice.
Consistent with the requirement for a written understanding regarding animal care and use, the JACKSON Animal Care and Use Committee will review the animal care and use protocol(s) associated with any SERVICES to be performed at JACKSON, and JACKSON shall have ultimate responsibility and authority for the care of animals while on site or in JACKSON custody.
In no event shall JACKSON, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, PRODUCTS, or SERVICES, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of JACKSON, its agents or employees. Unless prohibited by law, in purchasing or receiving MICE, PRODUCTS, or SERVICES from JACKSON, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges JACKSON from all such causes of action or damages, and further agrees to defend and indemnify JACKSON from any costs or damages arising out of any third party claims.
MICE, PRODUCTS or SERVICES are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.
The foregoing represents the General Terms and Conditions applicable to JACKSON’s MICE, PRODUCTS or SERVICES. In addition, special terms and conditions of sale of certain MICE, PRODUCTS, or SERVICES may be set forth separately in JACKSON web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, PRODUCTS and SERVICES by JACKSON, and by its licensees and distributors.
Acceptance of delivery of MICE, PRODUCTS or SERVICES shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on JACKSON, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, PRODUCTS or SERVICES by JACKSON.