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 Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse Generation N1F2pN1 Generation Definitions   Donating Investigator Dr. Donald Steiner,   University of Chicago

Description
Mice that are heterozygous for the targeted mutation are viable and fertile. No gene product (mRNA or protein) is detected in the homozygotes by Northern blot analysis of hypothalamic tissue or Western blot analysis of pituitary and brain tissue. Homozygote mice experience perinatal lethality, as the number of homozygotes born is less than the expected Mendelian ratio, and high postnatal lethality. By postnatal day 3, homozygotes are smaller in size than littermates. By 6 weeks of age, the surviving homozygotes are approximately 60% of wildtype body weight. Homozygotes have chronic mild diarrhea with bulky moist stools. Pituitary growth hormone transcript levels are only 25-20% of normal levels. Somatotroph cells in the anterior pituitary are reduced in size and inactive. Insulin-like growth factor 1 serum levels are significantly reduced. Transcript (mRNA) levels are greatly increased for growth hormone-releasing hormone in the hypothalamus and proopiomelanocortin in the pituitary. Mature growth hormone releasing hormone levels are significantly reduced. Mature adrenocorticotropic hormone is not detected in the pituitary, although plasma corticosterone levels are normal. Glucagon–like peptide 1 and 2 are not detectable in the small intestine of homozygotes. Insulin producing beta islet cells from homozygotes exhibit abnormal m orphology and contain almost no mature insulin. Homozygotes exhibit hyperproinsulinenia but have normal glucose tolerance. Immunureactive mature Met-enkephalin and neuropeptide precursor VGF are reduced in brain tissue of homozygous animals. Heterozygotes are mildly obese, have a twofold increase in proinsulin levels in the pancreas and have a lengthened glycemic reponse to the glucose tolerance test. This mutant mouse strain may be useful in studies of neuroendocrine and neuropeptide processing, endocrine and metabolic defects and obesity without diabetes.

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exon 1 and upstream promoter elements. The construct was electroporated into 129X1/SvJ derived GSI-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting male chimeric animals were crossed to C57BL/6J female mice, and then crossed to CD1 outbred mice.

Control Information

	Control
	Wild-type from the colony
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Pcsk1

006699

C57BL/6J-Pcsk1N222D/J

View Strains carrying other alleles of Pcsk1     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Proprotein Convertase 1/3 Deficiency   (PCSK1)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Pcsk1^tm1Dfs/Pcsk1⁺

        involves: 129 * C57BL/6J

• growth/size phenotype
• obese
  • mild obesity   (MGI Ref ID J:78369)
• homeostasis/metabolism phenotype
• abnormal glucose tolerance
  • prolonged glycemic response in response to glucose tolerance test   (MGI Ref ID J:78369)
• decreased circulating insulin level
  • reduced levels of mature insulin   (MGI Ref ID J:78369)

Pcsk1^tm1Dfs/Pcsk1^tm1Dfs

        involves: 129 * C57BL/6J

• mortality/aging
• increased sensitivity to xenobiotic induced morbidity/mortality
  • in LPS-treated mice   (MGI Ref ID J:184882)
• partial postnatal lethality
  • high degree of postnatal lethality prior to 7 days of age   (MGI Ref ID J:78369)
• partial prenatal lethality
  • ratio of mutant homozygotes less than expected   (MGI Ref ID J:78369)
• immune system phenotype
• abnormal T-helper 1 cell differentiation
  • LPS treatment promotes TH1 differentiation   (MGI Ref ID J:184882)
• abnormal peritoneal macrophage morphology
  • following LPS treatment, peritoneal macrophage fail to exhibit a decrease in the number of peripheral vacuoles or an increase in phagolysosomal vacuoles unlike wild-type macrophage   (MGI Ref ID J:184882)
  • prior to LPS treatment, macrophage exhibit an increase in electron-dense vesicles compared with wild-type cells   (MGI Ref ID J:184882)
  • prior to and after LPS treatment, macrophage exhibit increased membrane projections compared with wild-type cells   (MGI Ref ID J:184882)
• abnormal spleen white pulp morphology
  • white pulp is more concentrated in the middle of the spleen with fusion of white pulp nodes and some nodes in the periphery unlike in wild-type mice   (MGI Ref ID J:184882)
• • abnormal spleen marginal zone morphology   (MGI Ref ID J:184882)
  • intermingled spleen red and white pulp   (MGI Ref ID J:184882)
• decreased T cell number
  • slight in the spleen   (MGI Ref ID J:184882)
• • decreased NK T cell number
    • slight in the spleen   (MGI Ref ID J:184882)
• decreased follicular dendritic cell number
  • mostly disappeared from nodes and the marginal zone   (MGI Ref ID J:184882)
• enlarged spleen   (MGI Ref ID J:184882)
• increased circulating interferon-gamma level
  • 30 times 8 hours after LPS treatment   (MGI Ref ID J:184882)
• increased circulating interleukin-1 beta level
  • 5-fold 4 hours after LPS treatment   (MGI Ref ID J:184882)
  • 2 times 8 hours after LPS treatment   (MGI Ref ID J:184882)
• increased circulating interleukin-10 level
  • 8 hours after LPS treatment   (MGI Ref ID J:184882)
• increased circulating interleukin-12 level
  • 4 and 8 hours after LPS treatment   (MGI Ref ID J:184882)
• increased circulating interleukin-6 level
  • 30 times 4 hours after LPS treatment   (MGI Ref ID J:184882)
  • 2-fold 8 hours after LPS treatment   (MGI Ref ID J:184882)
• increased circulating tumor necrosis factor level
  • 8 times 4 hours after LPS treatment   (MGI Ref ID J:184882)
• increased interleukin-1 beta secretion
  • 2.5-fold from PBS incubated macrophage   (MGI Ref ID J:184882)
  • however, macrophage stimulated with LPS for 4 hours exhibit normal IL1B secretion   (MGI Ref ID J:184882)
• increased lymphocyte cell number
  • in the splenic red pulp   (MGI Ref ID J:184882)
• increased susceptibility to endotoxin shock
  • with increased lethality, decreased mean arterial blood pressure and increased cytokine production   (MGI Ref ID J:184882)
• digestive/alimentary phenotype
• chronic diarrhea
  • chronic mild diarrhea with bulky, moist stools   (MGI Ref ID J:78369)
• growth/size phenotype
• decreased body weight
  • homozygotes can be identified three days after birth by smaller size   (MGI Ref ID J:78369)
  • by 6 weeks, body weight is 60% of wildtype   (MGI Ref ID J:78369)
• homeostasis/metabolism phenotype
• decreased adrenocorticotropin level
  • absence of mature ACTH in anterior and intermediate pituitary lobes   (MGI Ref ID J:78369)
  • POMC processing is impaired   (MGI Ref ID J:78369)
  • plasma corticosterone levels are normal   (MGI Ref ID J:78369)
• decreased circulating glucagon level
  • lacks mature glucagon   (MGI Ref ID J:78369)
• decreased circulating growth hormone level
  • mature growth hormone releasing hormone levels are low or undetectable   (MGI Ref ID J:78369)
• decreased circulating insulin level
  • hyperproinsulinemia   (MGI Ref ID J:78369)
  • reduced levels of mature insulin but normal glucose tolerance response   (MGI Ref ID J:78369)
• hypoglycemia
  • chronic   (MGI Ref ID J:78369)
• increased circulating interferon-gamma level
  • 30 times 8 hours after LPS treatment   (MGI Ref ID J:184882)
• increased circulating interleukin-1 beta level
  • 5-fold 4 hours after LPS treatment   (MGI Ref ID J:184882)
  • 2 times 8 hours after LPS treatment   (MGI Ref ID J:184882)
• increased circulating interleukin-10 level
  • 8 hours after LPS treatment   (MGI Ref ID J:184882)
• increased circulating interleukin-12 level
  • 4 and 8 hours after LPS treatment   (MGI Ref ID J:184882)
• increased circulating interleukin-6 level
  • 30 times 4 hours after LPS treatment   (MGI Ref ID J:184882)
  • 2-fold 8 hours after LPS treatment   (MGI Ref ID J:184882)
• increased circulating tumor necrosis factor level
  • 8 times 4 hours after LPS treatment   (MGI Ref ID J:184882)
• increased sensitivity to xenobiotic induced morbidity/mortality
  • in LPS-treated mice   (MGI Ref ID J:184882)
• cardiovascular system phenotype
• decreased mean systemic arterial blood pressure
  • in LPS-treated mice   (MGI Ref ID J:184882)
• cellular phenotype
• abnormal T-helper 1 cell differentiation
  • LPS treatment promotes TH1 differentiation   (MGI Ref ID J:184882)
• hematopoietic system phenotype
• abnormal T-helper 1 cell differentiation
  • LPS treatment promotes TH1 differentiation   (MGI Ref ID J:184882)
• abnormal peritoneal macrophage morphology
  • following LPS treatment, peritoneal macrophage fail to exhibit a decrease in the number of peripheral vacuoles or an increase in phagolysosomal vacuoles unlike wild-type macrophage   (MGI Ref ID J:184882)
  • prior to LPS treatment, macrophage exhibit an increase in electron-dense vesicles compared with wild-type cells   (MGI Ref ID J:184882)
  • prior to and after LPS treatment, macrophage exhibit increased membrane projections compared with wild-type cells   (MGI Ref ID J:184882)
• abnormal spleen white pulp morphology
  • white pulp is more concentrated in the middle of the spleen with fusion of white pulp nodes and some nodes in the periphery unlike in wild-type mice   (MGI Ref ID J:184882)
• • abnormal spleen marginal zone morphology   (MGI Ref ID J:184882)
  • intermingled spleen red and white pulp   (MGI Ref ID J:184882)
• decreased T cell number
  • slight in the spleen   (MGI Ref ID J:184882)
• • decreased NK T cell number
    • slight in the spleen   (MGI Ref ID J:184882)
• enlarged spleen   (MGI Ref ID J:184882)
• increased lymphocyte cell number
  • in the splenic red pulp   (MGI Ref ID J:184882)

Pcsk1^tm1Dfs/Pcsk1^tm1Dfs

        involves: 129

• homeostasis/metabolism phenotype
• abnormal hormone level
  • gastric ghrelin mRNA levels are elevated ~40% compared to controls   (MGI Ref ID J:117652)

View Research Applications

Research Applications

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

Diabetes and Obesity Research
Obesity Without Diabetes

Endocrine Deficiency Research

Metabolism Research

Neurobiology Research
Metabolic Defects

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Pcsk1tm1Dfs
Allele Name		targeted mutation 1, Donald F Steiner
Allele Type		Targeted (knock-out)
Common Name(s)		PC1/3;
Mutation Made By		Dr. Donald Steiner,   University of Chicago
Strain of Origin		129
Gene Symbol and Name		Pcsk1, proprotein convertase subtilisin/kexin type 1
Chromosome		13
Gene Common Name(s)		BDP; BMIQ12; NEC1; Nec-1; Nec1; PC1; PC3; Phpp-1; SPC3; neuroendocrine convertase 1; prehormone processing proteinase; prohormone convertase 1/3;
Molecular Note		Exon 1 and several putative transcription control elements were replaced with a neomycin selection cassette. The absence of transcript and protein in homozygous mutant mice was determined by Northern and Western blot analyses. [MGI Ref ID J:78369]

Genotyping

Genotyping Information

Genotyping Protocols

Pcsk1^tm1Dfs, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Zhu X; Zhou A; Dey A; Norrbom C; Carroll R; Zhang C; Laurent V; Lindberg I; Ugleholdt R; Holst JJ; Steiner DF. 2002. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci U S A 99(16):10293-8. [PubMed: 12145326]  [MGI Ref ID J:78369]

Additional References

Pcsk1^tm1Dfs related

Cain BM; Connolly K; Blum AC; Vishnuvardhan D; Marchand JE; Zhu X; Steiner DF; Beinfeld MC. 2004. Genetic inactivation of prohormone convertase (PC1) causes a reduction in cholecystokinin (CCK) levels in the hippocampus, amygdala, pons and medulla in mouse brain that correlates with the degree of colocalization of PC1 and CCK mRNA in these structuresin rat brain. J Neurochem 89(2):307-13. [PubMed: 15056274]  [MGI Ref ID J:108016]

Hardiman A; Friedman TC; Grunwald WC Jr; Furuta M; Zhu Z; Steiner DF; Cool DR. 2005. Endocrinomic profile of neurointermediate lobe pituitary prohormone processing in PC1/3- and PC2-Null mice using SELDI-TOF mass spectrometry. J Mol Endocrinol 34(3):739-51. [PubMed: 15956344]  [MGI Ref ID J:112500]

Refaie S; Gagnon S; Gagnon H; Desjardins R; D'Anjou F; D'Orleans-Juste P; Zhu X; Steiner DF; Seidah NG; Lazure C; Salzet M; Day R. 2012. Disruption of proprotein convertase 1/3 (PC1/3) expression in mice causes innate immune defects and uncontrolled cytokine secretion. J Biol Chem 287(18):14703-17. [PubMed: 22396549]  [MGI Ref ID J:184882]

Rehfeld JF; Zhu X; Norrbom C; Bundgaard JR; Johnsen AH; Nielsen JE; Vikesaa J; Stein J; Dey A; Steiner DF; Friis-Hansen L. 2008. Prohormone convertases 1/3 and 2 together orchestrate the site-specific cleavages of progastrin to release gastrin-34 and gastrin-17. Biochem J 415(1):35-43. [PubMed: 18554181]  [MGI Ref ID J:140372]

Ugleholdt R; Poulsen ML; Holst PJ; Irminger JC; Orskov C; Pedersen J; Rosenkilde MM; Zhu X; Steiner DF; Holst JJ. 2006. Prohormone convertase 1/3 is essential for processing of the glucose-dependent insulinotropic polypeptide precursor. J Biol Chem 281(16):11050-7. [PubMed: 16476726]  [MGI Ref ID J:112681]

Ugleholdt R; Zhu X; Deacon CF; Orskov C; Steiner DF; Holst JJ. 2004. Impaired intestinal proglucagon processing in mice lacking prohormone convertase 1. Endocrinology 145(3):1349-55. [PubMed: 14630721]  [MGI Ref ID J:105584]

Wardman JH; Zhang X; Gagnon S; Castro LM; Zhu X; Steiner DF; Day R; Fricker LD. 2010. Analysis of peptides in prohormone convertase 1/3 null mouse brain using quantitative peptidomics. J Neurochem 114(1):215-25. [PubMed: 20412386]  [MGI Ref ID J:161820]

Zhu X; Cao Y; Voogd K; Steiner DF. 2006. On the processing of proghrelin to ghrelin. J Biol Chem 281(50):38867-70. [PubMed: 17050541]  [MGI Ref ID J:117652]

Zhu X; Orci L; Carroll R; Norrbom C; Ravazzola M; Steiner DF. 2002. Severe block in processing of proinsulin to insulin accompanied by elevation of des-64,65 proinsulin intermediates in islets of mice lacking prohormone convertase 1/3. Proc Natl Acad Sci U S A 99(16):10299-304. [PubMed: 12136131]  [MGI Ref ID J:78368]

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, G200.

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice are bred as heterozygotes due to the perinatal and postnatal lethality of homozygote animals.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	Wild-type from the colony
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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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