Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Coisogenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse Generation ?+N1F0pN1 Generation Definitions   Donating Investigator Iris Lindberg,   University of Maryland, Baltimore

Important Note
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.

Description
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.

Development
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.

Control Information

	Control
	Wild-type from the colony
	002448 129S1/SvImJ	(approximate)
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Scg5^tm1Led/Scg5^tm1Led

        either: 129S6/SvEvTac or (involves: 129S6/SvEvTac * FVB) or (involves: 129S6/SvEvTac * C57BL/6)

• mortality/aging
• partial postnatal lethality
  • only about 11% survive to weaning   (MGI Ref ID J:53349)
• adipose tissue phenotype
• abnormal adipose tissue distribution
  • surviving mice show abnormal fat deposition on the back and around the neck   (MGI Ref ID J:53349)
  • retroperitoneal fat deposits   (MGI Ref ID J:77510)
• behavior/neurological phenotype
• convulsive seizures
  • convulsions occur just before death   (MGI Ref ID J:77510)
• polyphagia   (MGI Ref ID J:77510)
• cardiovascular system phenotype
• abnormal cardiovascular system morphology   (MGI Ref ID J:77510)
• • dystrophic cardiac calcinosis   (MGI Ref ID J:77510)
  • enlarged heart   (MGI Ref ID J:77510)
• hemorrhage
  • often significant bleeding into the abdomen   (MGI Ref ID J:53349)
• • bruising
    • mice are often easily bruised   (MGI Ref ID J:53349)
  • ecchymosis
    • mice are often ecchymotic   (MGI Ref ID J:53349)
  • hemothorax   (MGI Ref ID J:53349)
• endocrine/exocrine gland phenotype
• abnormal gland morphology   (MGI Ref ID J:53349)
• • abnormal adrenal gland morphology   (MGI Ref ID J:53349)
  • • adrenal cortical hyperplasia   (MGI Ref ID J:53349)
  • abnormal pancreatic islet morphology
    • increased beta and non-beta endocrine cell mass in the pancreas   (MGI Ref ID J:53349)
  • • increased pancreatic beta cell mass   (MGI Ref ID J:53349)
    • pancreatic islet hyperplasia
      • architecture of the islets is disrupted   (MGI Ref ID J:53349)
  • cryptorchism
    • undescended testes frequently   (MGI Ref ID J:77510)
  • small adenohypophysis
    • hypotrophy of the anterior pituitary   (MGI Ref ID J:77510)
• growth/size phenotype
• decreased body size
  • severely runted at 4-5 weeks of age   (MGI Ref ID J:53349)
• homeostasis/metabolism phenotype
• abnormal blood homeostasis
  • increased lactate levels in plasma   (MGI Ref ID J:77510)
• • abnormal circulating insulin level
    • delayed conversion of proinsulin I and II with increased proinsulin levels   (MGI Ref ID J:53349)
    • increased circulating levels of insulin-like material   (MGI Ref ID J:53349)
  • decreased circulating glucagon level
    • mature glucagons are eliminated and only limited levels of intermediate products are found   (MGI Ref ID J:53349)
  • decreased circulating magnesium level
    • levels are significantly decreased in plasma   (MGI Ref ID J:77510)
  • hypoglycemia   (MGI Ref ID J:53349)
  • increased circulating corticosterone level
    • 4X increase in serum corticosterone   (MGI Ref ID J:53349)
• abnormal glucose homeostasis
  • high levels of free tissue glucose in the liver and decreased free glucose in muscle   (MGI Ref ID J:77510)
• • abnormal circulating insulin level
    • delayed conversion of proinsulin I and II with increased proinsulin levels   (MGI Ref ID J:53349)
    • increased circulating levels of insulin-like material   (MGI Ref ID J:53349)
  • decreased circulating glucagon level
    • mature glucagons are eliminated and only limited levels of intermediate products are found   (MGI Ref ID J:53349)
  • hypoglycemia   (MGI Ref ID J:53349)
  • increased liver glycogen level
    • liver glycogen levels increased 5X   (MGI Ref ID J:77510)
• abnormal mineral level
  • levels are significantly decreased in heart while liver and brain levels are increased 2X   (MGI Ref ID J:77510)
• • decreased circulating magnesium level
    • levels are significantly decreased in plasma   (MGI Ref ID J:77510)
• decreased body temperature
  • hypothermia occurs in the hours just before death   (MGI Ref ID J:77510)
• increased adrenocorticotropin level
  • levels were increased 10-20% in the pituitary   (MGI Ref ID J:53349)
• immune system phenotype
• spleen atrophy
  • spleen was 1/5 normal size with an abnormal architecture   (MGI Ref ID J:53349)
  • part of a generalized lymphoid atrophy   (MGI Ref ID J:53349)
• liver/biliary system phenotype
• enlarged liver
  • significant hepatomegaly   (MGI Ref ID J:77510)
• hepatic necrosis   (MGI Ref ID J:77510)
• hepatic steatosis
  • yellow color to liver   (MGI Ref ID J:77510)
  • severe fat vacuolation and abnormal liver architecture   (MGI Ref ID J:53349)
• increased liver glycogen level
  • liver glycogen levels increased 5X   (MGI Ref ID J:77510)
• reproductive system phenotype
• cryptorchism
  • undescended testes frequently   (MGI Ref ID J:77510)
• respiratory system phenotype
• abnormal respiration   (MGI Ref ID J:77510)
• • respiratory distress
    • mice suffer from labored respiration in the last day before dying   (MGI Ref ID J:77510)
    • experience shortness of breath just before death   (MGI Ref ID J:77510)
• hemothorax   (MGI Ref ID J:53349)
• nervous system phenotype
• convulsive seizures
  • convulsions occur just before death   (MGI Ref ID J:77510)
• small adenohypophysis
  • hypotrophy of the anterior pituitary   (MGI Ref ID J:77510)
• integument phenotype
• abnormal hair growth   (MGI Ref ID J:77510)
• • alopecia
    • regional hair loss   (MGI Ref ID J:77510)
  • sparse hair   (MGI Ref ID J:77510)
• ecchymosis
  • mice are often ecchymotic   (MGI Ref ID J:53349)
• hyperkeratosis   (MGI Ref ID J:53349)
• pallor
  • mice are pale   (MGI Ref ID J:53349)
• thin dermal layer
  • dermal atrophy   (MGI Ref ID J:53349)
• thin skin
  • thinning skin   (MGI Ref ID J:53349)
• hematopoietic system phenotype
• spleen atrophy
  • spleen was 1/5 normal size with an abnormal architecture   (MGI Ref ID J:53349)
  • part of a generalized lymphoid atrophy   (MGI Ref ID J:53349)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Cardiovascular Research
Other
      altered fat metabolism

Developmental Biology Research
Perinatal Lethality
      Homozygous

Diabetes and Obesity Research
Hyperinsulinemia
Hypoglycemia

Endocrine Deficiency Research
Adrenal Cortex Defects
Adrenal Medulla Defects
Hypothalamus/Pituitary Defects

Internal/Organ Research
Adrenal Cortex Defects
Adrenal Medulla Defects

Metabolism Research
Lipid Metabolism

Research Tools
Cardiovascular Research
Diabetes and Obesity Research
Endocrine Deficiency Research
Internal/Organ Research
Metabolism Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Scg5tm1Led
Allele Name		targeted mutation 1, Philip Leder
Allele Type		Targeted (knock-out)
Common Name(s)		7B2 KO;
Mutation Made By		Philip Leder,   Harvard Medical School
Strain of Origin		129S6/SvEvTac
ES Cell Line Name		TC1/TC-1
ES Cell Line Strain		129S6/SvEvTac
Gene Symbol and Name		Scg5, secretogranin V
Chromosome		2
Gene Common Name(s)		7B2; AI325031; P7B2; SGNE1; SgV; Sgne-1; Sgne1; expressed sequence AI325031; secretory granule neuroendocrine protein 1, 7B2 protein;
General Note		Phenotypic Similarity to Human Syndrome: Pituitary ACTH Hypersecretion (MeSH:C10.228.140.617.738.250.725) 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. [MGI Ref ID J:42189]

Genotyping

Genotyping Information

Genotyping Protocols

Generic Neo Melt Curve Analysis, Melt Curve Analysis
Generic Neo Melt Curve Analysis, Robotic MCA
Scg5^tm1Led, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Sarac MS; Zieske AW; Lindberg I. 2002. The lethal form of Cushing's in 7B2 null mice is caused by multiple metabolic and hormonal abnormalities. Endocrinology 143(6):2324-32. [PubMed: 12021197]  [MGI Ref ID J:77510]

Westphal CH; Muller L; Zhou A; Zhu X; Bonner-Weir S; Schambelan M; Steiner DF; Lindberg I; Leder P. 1999. The neuroendocrine protein 7B2 is required for peptide hormone processing in vivo and provides a novel mechanism for pituitary Cushing's disease. Cell 96(5):689-700. [PubMed: 10089884]  [MGI Ref ID J:53349]

Additional References

Scg5^tm1Led related

Elson AE; Dotson CD; Egan JM; Munger SD. 2010. Glucagon signaling modulates sweet taste responsiveness. FASEB J 24(10):3960-9. [PubMed: 20547661]  [MGI Ref ID J:165308]

Helwig M; Lee SN; Hwang JR; Ozawa A; Medrano JF; Lindberg I. 2011. Dynamic Modulation of Prohormone Convertase 2 (PC2)-mediated Precursor Processing by 7B2 Protein: PREFERENTIAL EFFECT ON GLUCAGON SYNTHESIS. J Biol Chem 286(49):42504-13. [PubMed: 22013069]  [MGI Ref ID J:178715]

Laurent V; Jaubert-Miazza L; Desjardins R; Day R; Lindberg I. 2004. Biosynthesis of proopiomelanocortin-derived peptides in prohormone convertase 2 and 7B2 null mice. Endocrinology 145(2):519-28. [PubMed: 14576186]  [MGI Ref ID J:88673]

Laurent V; Kimble A; Peng B; Zhu P; Pintar JE; Steiner DF; Lindberg I. 2002. Mortality in 7B2 null mice can be rescued by adrenalectomy: involvement of dopamine in ACTH hypersecretion. Proc Natl Acad Sci U S A 99(5):3087-92. [PubMed: 11854475]  [MGI Ref ID J:126986]

Peinado JR; Laurent V; Lee SN; Peng BW; Pintar JE; Steiner DF; Lindberg I. 2005. Strain-dependent influences on the hypothalamo-pituitary-adrenal axis profoundly affect the 7B2 and PC2 null phenotypes. Endocrinology 146(8):3438-44. [PubMed: 15878971]  [MGI Ref ID J:129821]

Rehfeld JF; Lindberg I; Friis-Hansen L. 2002. Progastrin processing differs in 7B2 and PC2 knockout animals: a role for 7B2 independent of action on PC2. FEBS Lett 510(1-2):89-93. [PubMed: 11755537]  [MGI Ref ID J:73621]

Sarac MS; Windeatt S; Castro MG; Lindberg I. 2002. Intrapituitary adenoviral administration of 7B2 can extend life span and reverse endocrinological deficiencies in 7B2 null mice. Endocrinology 143(6):2314-23. [PubMed: 12021196]  [MGI Ref ID J:77509]

Vishnuvardhan D; Connolly K; Cain B; Beinfeld MC. 2000. PC2 and 7B2 null mice demonstrate that PC2 is essential for normal pro-CCK processing. Biochem Biophys Res Commun 273(1):188-91. [PubMed: 10873584]  [MGI Ref ID J:62889]

Westphal CH; Leder P. 1997. Transposon-generated 'knock-out' and 'knock-in' gene-targeting constructs for use in mice. Curr Biol 7:530-3. [PubMed: 9210379]  [MGI Ref ID J:42189]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, RG10/RG30.

Colony Maintenance

Breeding & Husbandry

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.

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Wild-type from the colony
	002448 129S1/SvImJ	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

Important Note

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.

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Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

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The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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