Description

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System +/+ sibling x Heterozygote         (Female x Male) Species laboratory mouse Generation N1F1 (03-JUN-07)   Donating Investigator 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 Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

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

Pcsk1^tm1Dfs/Pcsk1⁺

        involves: 129/Sv * C57BL/6J

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

Pcsk1^tm1Dfs/Pcsk1^tm1Dfs

        involves: 129/Sv * C57BL/6J

• lethality-prenatal/perinatal
• prenatal lethality (MGI Ref ID J:78369)
  • ratio of mutant homozygotes less than expected
• lethality-postnatal
• postnatal lethality (MGI Ref ID J:78369)
  • high degree of postnatal lethality prior to 7 days of age
• digestive/alimentary phenotype
• chronic diarrhea (MGI Ref ID J:78369)
  • chronic mild diarrhea with bulky, moist stools
• growth/size phenotype
• decreased body weight (MGI Ref ID J:78369)
  • homozygotes can be identified three days after birth by smaller size
  • by 6 weeks, body weight is 60% of wildtype
• homeostasis/metabolism phenotype
• decreased adrenocorticotropin level (MGI Ref ID J:78369)
  • absence of mature ACTH in anterior and intermediate pituitary lobes
  • POMC processing is impaired
  • plasma corticosterone levels are normal
• decreased circulating glucagon level (MGI Ref ID J:78369)
  • lacks mature glucagon
• decreased circulating growth hormone level (MGI Ref ID J:78369)
  • mature growth hormone releasing hormone levels are low or undetectable
• decreased circulating insulin level (MGI Ref ID J:78369)
  • hyperproinsulinemia
  • reduced levels of mature insulin but normal glucose tolerance response
• hypoglycemia (MGI Ref ID J:78369)
  • chronic

Pcsk1^tm1Dfs/Pcsk1^tm1Dfs

        involves: 129/Sv

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

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

Allele Symbol		Pcsk1tm1Dfs
Allele Name		targeted mutation 1, Donald F Steiner
Allele Type		Targeted (knock-out)
Common Name(s)		PC1/3;
Mutation Made By		Donald Steiner,   University of Chicago
Strain of Origin		129/Sv
Gene Symbol and Name		Pcsk1, proprotein convertase subtilisin/kexin type 1
Chromosome		13
Gene Common Name(s)		BDP; 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 deleted by the insertion of 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, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

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]

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]

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

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

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.
Mating System	+/+ sibling x Heterozygote         (Female x Male)
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.

Supply Notes

Usually shipped between four and eight weeks of age. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Wild-type from the colony
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

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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Ordering and Purchasing Information

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Contact Information
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Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
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Terms of Use

Terms of Use

General Terms and Conditions

Contact information

General inquiries

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phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (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 with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

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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 The Jackson Laboratory, 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 services by The Jackson Laboratory.