These double mutant mice harbor both the spontaneous Leprdb mutation and nitric oxide synthase 3, endothelial cell (Nos3 or eNOS) targeted mutation. Double homozygous eNOS-/- C57BLKS/J db/db mice (also called eNOS-/- db/db, or db/db/eNOS-/- double mutant mice) are a robust model of type II diabetic nephropathy and may be useful for studying eNOS-mediated events in the development and progression of diabetic nephropathy.
Dr. Raymond C. Harris, Vanderbilt University Med Center
These double mutant mice harbor both the Leprdb spontaneous mutation and the Nos3 (eNOS) targeted mutation and are congenic on C57BLKS/J genetic background. Mice homozygous for both mutations (called eNOS-/- C57BLKS/J db/db, eNOS-/- db/db, or db/db/eNOS-/- double mutant mice) are viable with development of type II diabetes and diabetic nephropathy. The eNOS-/- C57BLKS/J db/db mice develop type II diabetes with significant obesity and hypertension: while both mutations are associated with insulin resistance, the mutated leptin receptor in db/db mice chiefly accounts for the observed hyperglycemia and defective leptin signaling (leading to persistent hyperphagia and obesity), and the eNOS-deficiency accounts for the moderate systemic hypertension. In addition, eNOS-/- C57BLKS/J db/db mice exhibit rapid onset and progression of pathologic diabetic nephropathy (DN) features by 26 weeks of age; developing severe albuminuria and other DN characteristics (including arteriolar hyalinosis, increased glomerular basement membrane thickness, mesangial expansion, mesangiolysis, and focal segmental and early nodular glomerulosclerosis), also with remarkably decreased glomerular filtration rate (GFR; on the basis of impaired inulin clearance and increased serum creatinine). Double homozygous eNOS-/- C57BLKS/J db/db mice are a robust model of type II diabetic nephropathy and may be useful for studying eNOS-mediated events in the development and progression of diabetic nephropathy.
These eNOS- C57BLKS/J Leprdb double mutant mice were generated in the laboratory of Dr. Raymond C. Harris (Vanderbilt University) by backcrossing eNOS-mutant mice (Stock No. 002684) to C57BLKS/J inbred mice (Stock No. 000662) for 10 generations, and then the resulting mice were bred with the BKS.Cg-Dock7m +/+ Leprdb/J repulsion stock (Stock No. 000642). Mice homozygous for the eNOS mutation, heterozygous for Leprdb, and segregating for misty (m) were sent to The Jackson Laboratory. Upon arrival, mice were bred with C57BLKS/J inbred mice (Stock No. 000662) to establish this colony (and remove misty).
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. One marker on Chromosome 5 was still segregating with the targeted mutation. Two markers on Chromosome 11 were found to still be segregating with C57BL/6J as in parental line Stock No. 002684.
|Allele Synonym(s)||Lepdb; Lepr-; Leprdb-1J; db; db/db; leprdb|
|Gene Symbol and Name||Lepr, leptin receptor|
|Gene Synonym(s)||CD295; Fa; LEP-R; LEPRD; LEPROT; Leprb; Modb1; OB-R; OB-RGRP; OBR; Obr; db; diabetes; leptin receptor gene-related protein; obese-like; obese-like; obl; obl|
|Strain of Origin||C57BLKS/J|
|General Note|| |
Phenotypic Similarity to Human Syndrome: Gestational Diabetes J:219658
|Molecular Note||A G-to-T transversion in this allele created a donor splice site that causes abnormal splicing and a 106 nt insertion in the transcript, leading to premature termination of the long cellular domain of the Ob-Rb splice form and loss of its signal transducing function.|
|Allele Name||targeted mutation 1, University of North Carolina|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||NOS3-; eNOS-; eNOSKO; ecNOS-|
|Gene Symbol and Name||Nos3, nitric oxide synthase 3, endothelial cell|
|Gene Synonym(s)||2310065A03Rik; 2310065A03Rik; ECNOS; Nos-3; Nos-3; RIKEN cDNA 2310065A03 gene; eNOS; eNos; ecNOS; nitric oxide synthase 3 (indicible)|
|Strain of Origin||129P2/OlaHsd|
|Molecular Note||A 1.2 kb neomycin cassette replaced 129 bp of exon 12 of the gene. This disrupted the calmodulin binding site of the protein and introduced a premature stop codon into the transcripts. Immunohistochemisty of heart and kidney sections from homozygous mutant mice confirmed that no detectable encoded protein was present.|
|Mutations Made By|| |
Dr. Oliver Smithies, University of North Carolina at Chapel Hill
When maintaining a live colony, mice heterozygous for the Leprdb spontaneous mutation and homozygous for the Nos3 (eNOS-/-) targeted mutation may be bred together. NOTE: These mice have significant breeding difficulties. Approximately 16% of Het Hom x Het Hom matings are non-productive; approximately 23% of females only produce one litter; pre-wean loss is approximately 10%; 20% of breeders are found dead prior to retirement at 6-8 months of age.
When using the eNOS-/- C57BLKS/J db mouse strain in a publication, please cite the originating article(s) and include JAX stock #008340 in your Materials and Methods section.
|Heterozygous or wildtype for Lepr<db>and Heterozygous for Nos3<tm1Unc>|
The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided,
their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of
each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders
are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in
order to provide the minimum number of animals, animals will ship within 25 weeks.
The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory 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.