These "7B2" mutant mice may be useful in studies of corticosterone excess and its profound developmental effects, Cushing's disease, and other neuro-endocrine, obesity, or metabolism research. However, it should be noted that the phenotype of the 7B2-null mice on a mixed 129S genetic background distributed by The Jackson Laboratory Repository could vary from that originally described for 7B2-null mice with a different 129S genetic background.
Iris Lindberg, University of Maryland, Baltimore
The colony at The Jackson Laboratory Repository is on a mixed 129S genetic background and may not recapitulate the phenotype originally described for mutant mice with a different 129S genetic background.
The colony at The Jackson Laboratory Repository is on a mixed 129S genetic background and may not recapitulate the phenotype originally described.
The following text reflects the phenotype reported by the donating investigator (Dr. Iris Lindberg) on a "129Sv" genetic background (probably "Taconic Sv129" (129S6/SvEvJ)).
While heterozygotes are viable and fertile, mice homozygous for this mutation (7B2-null) die in prepubertal or pubertal ages (5 weeks) with severe cardio-respiratory failure, convulsions, and hypothermia. No transcripts are detected in brain tissue from the targeted gene. 7B2-null mice are unable to make an active form of prohormone convertase 2 (PC2) and have high circulating corticosterone. Homozygotes on the "129Sv" genetic background exhibit Cushing's-like disease pathologies of liver, pancreas, and pituitary; including pituitary-dependent hyperadrenocorticosteronism, severe hypoglycemia, hyperproinsulinemia, adrenal hypertrophy, pituitary hypotrophy, and altered islet cell morphology. 7B2-null mice develop the disease from intermediate lobe ACTH hypersecretion (rather than from pituitary adenomas). Other abnormalities include thinning fur, thin tail, skeletal defects, dorsal and intraperitoneal adipose deposits, low blood sugar, fatty liver, and inability to synthesize glucagon. The donating investigator reports that null pups on the 129/SvEv genetic background are distinguishable by appearance, do not compete well for milk, and suggests thinning litters to 1-2 mice to obtain homozygotes.
In 2008, 7B2-null mice on the mixed 129S genetic background were sent from The Jackson Laboratory Repository colony back to the donating investigator (Dr. Iris Lindberg; now at University of Maryland). In November 2010, Dr. Lindberg reported that 7B2-null mice no longer exhibit the lethal phenotype observed for 7B2-null mice on a "129Sv" genetic background (probably "Taconic Sv129" (129S6/SvEvJ)). The cause of this is not known; but may be due to 129 substrain differences and/or husbandry changes in different vivaria, or other. In addition, Dr. Lindberg backcrossed the mice onto "the Taconic 129Sv background" for eight generations and was unable to recapitulate the homozygous lethal phenotype. Therefore, the 7B2-null mice on the mixed 129S genetic background distributed from The Jackson Laboratory Repository may no longer represent a Cushing's disease model.
These 7B2-null mice may be useful in studies of corticosterone excess and its profound developmental effects, Cushing's disease, and other neuro-endocrine, obesity, or metabolism research. However, it should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.
A transposon-based gene targeting approach was designed to interrupt exon 3 of the targeted gene by random integration of a transposon and subsequent introduction of a neo cassette. The construct was electroporated into 129/SvEv embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric males were crossed with 129/SvEv females. Heterozygous mice on this 129/SvEv genetic background were bred together for many generations prior to arrival at The Jackson Laboratory Repository. Upon arrival, mutant mice were bred with 129S1/SvImJ (Stock No. 002448) for at least one generation to rederive and establish the Jackson Laboratory Repository colony. After this, sperm from heterozygous males was cryopreserved.
|Allele Name||targeted mutation 1, Philip Leder|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||7B2 KO|
|Gene Symbol and Name||Scg5, secretogranin V|
|Strain of Origin||129S6/SvEvTac|
|General Note|| |
Unlike classical Cushing's disease, which results from excess ACTH secretion from pituitary adenomas, null mice develop this disease from intermediate lobe ACTH hypersecretion. (J:77510)
|Molecular Note||Insertion of a neomycin resistance cassette placed an artificial transposon after the eightieth base pair of exon 3 and disrupted the gene. Northern analysis of brain did not detect transcript in homozygous mice.|
|Mutations Made By|| |
Dr. Philip Leder, Harvard Medical School
When maintaining a live colony, these mice are bred as heterozygotes. These mice are on a mixed 129S genetic background. The published phenotype of homozygous mice (on a "129Sv" genetic background (probably "Taconic Sv129" (129S6/SvEvJ)) die around 5 weeks of age. The donating investigator reports that null pups are distinguishable by appearance, do not compete well for milk, and suggests thinning litters to 1-2 mice to obtain homozygotes.
When using the 129S-Scg5tm1Led/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #007005 in your Materials and Methods section.
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