These Eif2s1 knock-out mice lack translational and transcriptional regulation in the endoplasmic reticulum. These mice maybe useful in diabetes research.
Randal J Kaufman, Sanford Burnham Prebys Medical Discovery Institute
The Eif2aS51A mutation in these mice prevents phosphorylation of the α subunit of eIF2. Phosphorylation of eIF2α in the endoplasmic reticulum (ER) is required for translational regulation, transcriptional induction, and survival in response to ER stress. EIF2α translational regulation is also required for the maintenance of blood glucose and pancreatic insulin content. Homozygotes die within 18 hr after birth due to hypoglycemia associated with defective gluconeogenesis. Homozygous mutant embryos and neonates displayed a deficiency in pancreatic β cells and an increase in circulating insulin. Heterozygotes are viable and fertile. On a high fat diet, heterozygous mice develop diabetes due to unregulated proinsulin translation. These mice also exhibit defective ER cargo trafficking, increased oxidative damage, reduced expression of stress response and beta-cell-specific genes, and apoptosis.
Three base pair substitutions were introduced into exon 2 of the mouse eIF2α (Eif2s1) resulting in a single amino acid substitution of serine to alanine at codon 51 (S51A) within the phosphorylation site of the protein. A loxP-flanked neo cassette in reverse-orientation to the gene was inserted 200 bp upstream of exon 2. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-Kitl+-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient C57BL/6 blastocysts and chimeric males were bred with C57BL/6 females to establish the colony. Mutant mice were bred with ZP3-Cre transgenic mice (on a C57BL/6 genetic background) to remove the neo selection cassette. The donating investigator reported that these eIF2αS51A mice were bred to C57BL/6J mice for at least ten generations (see SNP note below), and the ZP3-Cre transgene was removed. Upon arrival at The Jackson Laboratory Repository, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.
A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. 2 the 27 markers throughout the genome were segregating between B6J and 129, suggesting an incomplete backcross. Also, 4 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.
|Allele Name||targeted mutation 1, Randal J Kaufman|
|Allele Type||Targeted (Not Specified)|
|Allele Synonym(s)||Eif2s1tm1Rjk; targeted mutation 1, Randal J Kaufman|
|Gene Symbol and Name||Eif2s1, eukaryotic translation initiation factor 2, subunit 1 alpha|
|Gene Synonym(s)||eukaryotic translation initiation factor 2A; 0910001O23Rik; 2410026C18Rik; 0910001O23Rik; Eif2a; EIF-2; EIF-2A; EIF-2alpha; EIF2; EIF2A; eIF2alpha; RIKEN cDNA 0910001O23 gene; RIKEN cDNA 2410026C18 gene; 2410026C18Rik; Eif2a|
|Promoter||Eif2s1, eukaryotic translation initiation factor 2, subunit 1 alpha, mouse, laboratory|
|Strain of Origin||(129X1/SvJ x 129S1/Sv)F1-Kitl+|
|Molecular Note||A serine to alanine substitution at a phosphorylation site at position 51 (S51A) of exon 2 was introduced, and a floxed neomycin resistance cassette was inserted into the upstream intron for positive selection. The floxed neo cassette was removed by cre-mediated recombination leaving behind a single loxP site and the S51A mutation. Western blot analysis of mouse embryonic fibroblasts derived from homozygous mutant animals confirmed expression of the mutant allele.|
|Mutations Made By|| |
Randal Kaufman, Sanford Burnham Prebys Medical Discovery Institute
When maintaining a live colony, heterozygous mice may be bred to wildtype mice from the colony or to C57BL/6J inbred mice (Stock No. 000664). The donating investigator reports that homozygotes die within 18 hours after birth due to hypoglycemia. Heterozygous offspring survival is enhanced if cages containing newborns are not disturbed in the first 3 days after birth.
When using the eIF2alphaS51A mouse strain in a publication, please cite the originating article(s) and include JAX stock #017601 in your Materials and Methods section.
|Heterozygous or wildtype for Eif2s1<tm1Rjk>|
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.