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

Former Names STOCK Ipf1tm1Macd/J    (Changed: 15-DEC-06 ) Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse Generation ?+N1p   Donating Investigator Raymond MacDonald,   UTSW Medical Center

Description
Mice homozygous for the targeted mutation fail to develop a pancreas. Heterozygous mice have normal pancreas development but partially impaired glucose tolerance in adulthood. The substitution of the targeted gene with tTA_off inactivates the endogenous allele and places tTA_off expression under the control of the endogenous transcriptional regulatory sequences. tTA expression from the modified locus is identical to that of the normal allele; tTA mRNA is detectable in the pancreas but not in other visceral organs or salivary glands. This mutant may be useful in studies of pancreatic endocrine/exocrine function and diabetes. Heterozygotes also can be bred with transgenic mice that express a target gene under the regulation of a tetracycline-responsive element (TRE; tetO) for pancreas-specific applications.

This mutant was originally designed to be mated with mutant mice with a TRE-controlled transgene coding for the endogenous Pdx1 (Ipf1) gene along with a reporter (EGFP or beta-galactosidase gene, (see Stock No. 005699 and 005728 respectively).

Development
A targeting vector containing a tetracycline-responsive tet-repressor/VP16 fusion transactivator (tTA_off) and the neomycin-resistance gene flanked with 4.5-kb upstream and 1.3-kb downstream homology domains was used to replace the entire coding region (both exons and the intron) of the endogenous Pdx1 locus. The construct was electroporated into the (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric males were bred with C57BL/6 females to generate heterozygotes. At some point, mutant mice were bred to B6SJL hybrid transgenic mice. The transgene was selected against in subsequent breedings, and strain is now maintained as heterozygous for the Pdx1 targeted mutation.

Control Information

	Control
	Wild-type from the colony
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Pdx1

005699	STOCK Tg(tetO-Ipf1,EGFP)956.6Macd/J
005728	STOCK Tg(tetO-Ipf1,lacZ)958.1Macd/J

View Strains carrying other alleles of Pdx1     (2 strains)

Additional Web Information

Tet Expression Systems

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.

Pdx1^tm1Macd/Pdx1⁺

        involves: 129S1/Sv * 129X1/SvJ

• homeostasis/metabolism phenotype
• impaired glucose tolerance (MGI Ref ID J:79206)
  • heterozygotes display partially impaired glucose tolerance compared to wild-type mice; doxycycline treatment has no effect
  • heterozygotes display partially impaired early response to glucose challenge compared to wild-type mice; ability to recover after glucose challenge is impaired

Pdx1^tm1Macd/Pdx1^tm1Macd

        involves: 129S1/Sv * 129X1/SvJ

• liver/biliary system phenotype
• *normal* liver/biliary system phenotype (MGI Ref ID J:151981)
  • mice exhibit normal development of the gall bladder, collecting ducts, and common duct

The following phenotype relates to a compound genotype created using this strain.
Contact JAX^® Services jaxservices@jax.org for customized breeding options.

Pdx1^tm1Macd/Pdx1^tm1Macd Tg(tetO-Ipf1,EGFP)956.6Macd/0

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL

• homeostasis/metabolism phenotype
• decreased circulating glucose level (MGI Ref ID J:101742)
  • 14 days after doxycycline withdrawal after 14 days of treatment resulted in a significant decrease in blood glucose levels with 4/5 mice becoming normoglycemic by 28 days
• impaired glucose tolerance (MGI Ref ID J:79206)
  • adult transgenic rescue animals treated with doxycycline for 14 days exhibit a defective response to glucose challenge compared to wild-type, non mutant transgenic, or untreated rescue mice
  • when adult mice are treated with doxycycline for 0, 7, 14, or 21 days, mice show an increased early glucose response within 7 days of start of treatment and ability to recover from glucose challenge is impaired compared to untreated transgenics where glucose levels recover to basal levels within 3 hours; by 14 days of doxycycline treatment, mice have diabetes
• increased circulating glucose level (MGI Ref ID J:79206)
  • with doxycycline treatment for 21 day, adult rescue mice show a 4-fold increase in fasting blood glucose to diabetic levels
• endocrine/exocrine gland phenotype
• abnormal pancreas development (MGI Ref ID J:79206)
  • pancreas of transgenic rescue newborn mice is 50% the size of a normal wild-type neonatal pancreas
  • treatment of pregnant mice with doxycycline from the first day of pregnancy through parturition prevents formation of the pancreas in mice with the transgenic rescue genotype
  • treatment on E11.5 arrests pancreatic development ~36 hours later; at birth the underdeveloped remnant consisted of a large and extended duct with several terminal, aborted, ductal buds with ducts lined with a single layer of primitive epithelial cells and with no acinar or islet tissue
• abnormal pancreatic beta cell morphology (MGI Ref ID J:101742)
  • after 14 or 28 days of dox treatment there are, still present, beta cells which lack insulin
• decreased insulin secretion (MGI Ref ID J:101742)
  • there is a marked reduction in insulin in pancreata of doxycycline-treated mice; after withdrawal of doxycycline, insulin +ve cells are detected in islets of smaller islet-like cell clusters
• increased glucagon secretion (MGI Ref ID J:101742)
  • in doxycycline-treated mice there is an increase in glucagons-positive cells
• small pancreatic islets (MGI Ref ID J:101742)
  • after dox treatment for 14 days, there is a significant decrease in islet area compared to wild-type
• digestive/alimentary phenotype
• abnormal pancreas development (MGI Ref ID J:79206)
  • pancreas of transgenic rescue newborn mice is 50% the size of a normal wild-type neonatal pancreas
  • treatment of pregnant mice with doxycycline from the first day of pregnancy through parturition prevents formation of the pancreas in mice with the transgenic rescue genotype
  • treatment on E11.5 arrests pancreatic development ~36 hours later; at birth the underdeveloped remnant consisted of a large and extended duct with several terminal, aborted, ductal buds with ducts lined with a single layer of primitive epithelial cells and with no acinar or islet tissue
• abnormal pancreatic beta cell morphology (MGI Ref ID J:101742)
  • after 14 or 28 days of dox treatment there are, still present, beta cells which lack insulin
• decreased insulin secretion (MGI Ref ID J:101742)
  • there is a marked reduction in insulin in pancreata of doxycycline-treated mice; after withdrawal of doxycycline, insulin +ve cells are detected in islets of smaller islet-like cell clusters
• increased glucagon secretion (MGI Ref ID J:101742)
  • in doxycycline-treated mice there is an increase in glucagons-positive cells
• small pancreatic islets (MGI Ref ID J:101742)
  • after dox treatment for 14 days, there is a significant decrease in islet area compared to wild-type
• cellular phenotype
• increased cell proliferation (MGI Ref ID J:101742)
  • foci of duct proliferation are present in mice after 14 days of doxycycline treatment and become more prominent with continued treatment

Pdx1^tm1Macd/Pdx1^tm1Macd Tg(tetO-Ipf1,lacZ)958.1Macd/0

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL

• homeostasis/metabolism phenotype
• impaired glucose tolerance (MGI Ref ID J:103522)
  • transgenic mice gradually attain an impaired glucose tolerance response to glucose challenge
• endocrine/exocrine gland phenotype
• abnormal pancreas development (MGI Ref ID J:103522)
  • when dams are treated with doxycycline from conception through birth, only small epithelial remnants of the pancreas form; treatment at E7.5 or E8.5 results in the same phenotype
  • doxycycline from E9.5 diminishes epithelial morphogenesis; treatement from E9.5 allows outgrowth of a linear epithelial tube with nascent invaginations representing initial primary branching
  • treatment from E11.5 allows the formation of a larger crude duct-like structure with a few distal primary branches; treatement from E12.5 permits formation of extensive fine structure consisting of immature acini and associated small ductules
  • with treatment from E12.5, pancreatic dorsal and ventral remnants composed of convoluted partially branched duct-like epithelium of columnar epithelium are present, and show a block at the stage of acinar cell formation
  • examination of embryo ductal remnants from mice treated with dox from E11.5 show an absence of preacini; treatment from E12.5 results in a larger remnant with a smaller proportion of primitive duct; the epithelium is replaced by numerous eosinophilic clusters lacking ductal markers which are polarized, arranged around a central lumen and resemble immature acini
• absent pancreas (MGI Ref ID J:103522)
  • ~1/5 pups are born without a pancreas; rescue of pancreas formation is observed in ~80% of transgenic mice
• digestive/alimentary phenotype
• abnormal pancreas development (MGI Ref ID J:103522)
  • when dams are treated with doxycycline from conception through birth, only small epithelial remnants of the pancreas form; treatment at E7.5 or E8.5 results in the same phenotype
  • doxycycline from E9.5 diminishes epithelial morphogenesis; treatement from E9.5 allows outgrowth of a linear epithelial tube with nascent invaginations representing initial primary branching
  • treatment from E11.5 allows the formation of a larger crude duct-like structure with a few distal primary branches; treatement from E12.5 permits formation of extensive fine structure consisting of immature acini and associated small ductules
  • with treatment from E12.5, pancreatic dorsal and ventral remnants composed of convoluted partially branched duct-like epithelium of columnar epithelium are present, and show a block at the stage of acinar cell formation
  • examination of embryo ductal remnants from mice treated with dox from E11.5 show an absence of preacini; treatment from E12.5 results in a larger remnant with a smaller proportion of primitive duct; the epithelium is replaced by numerous eosinophilic clusters lacking ductal markers which are polarized, arranged around a central lumen and resemble immature acini
• absent pancreas (MGI Ref ID J:103522)
  • ~1/5 pups are born without a pancreas; rescue of pancreas formation is observed in ~80% of transgenic mice

View Research Applications

Research Applications

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

Endocrine Deficiency Research
Pancreas Defects

Metabolism Research
Enzyme Deficiency
      exocrine pancreatic insufficiency

Research Tools
Endocrine Deficiency Research
Genetics Research
      Tissue/Cell Markers: multiple
      Tissue/Cell Markers: pancreatic beta cells
Tet Expression Systems
      tTA/rtTA Expressing Strains

Genes & Alleles

Gene & Allele Information

Allele Symbol		Pdx1tm1Macd
Allele Name		targeted mutation 1, Raymond J MacDonald
Allele Type		Targeted (knock-in)
Common Name(s)		Pdx1tTA;
Mutation Made By		Raymond MacDonald,   UTSW Medical Center
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
ES Cell Line Name		R1
ES Cell Line Strain		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Site of Expression		Expresses tTA in pancreas.
Gene Symbol and Name		Pdx1, pancreatic and duodenal homeobox 1
Chromosome		5
Gene Common Name(s)		GSF; IDX-1; IPF-1; IPF1; IUF1; Idx1; Ipf1; MODY4; PDX-1; STF-1; Stf1; insulin promoter factor 1; insulin promoter factor 1, homeodomain transcription factor; pancreatic and duodenal homeobox gene 1;
Molecular Note		Exons 1 and 2, which encompass the entire coding region, were replaced with a cassette containing a tetracycline transactivator (tTA) and a neo resistance gene. RT-PCR showed tTA expression in adult pancreas tissue but not in other visceral organs or salivary glands. [MGI Ref ID J:79206]

Genotyping

Genotyping Information

Genotyping Protocols

Pdx1^tm1Macd, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References

Selected Reference(s)

Holland AM; Hale MA; Kagami H; Hammer RE; MacDonald RJ. 2002. Experimental control of pancreatic development and maintenance. Proc Natl Acad Sci U S A 99(19):12236-41. [PubMed: 12221286]  [MGI Ref ID J:79206]

Additional References

Pdx1^tm1Macd related

Brennand K; Huangfu D; Melton D. 2007. All beta Cells Contribute Equally to Islet Growth and Maintenance. PLoS Biol 5(7):e163. [PubMed: 17535113]  [MGI Ref ID J:124045]

Gauthier BR; Wiederkehr A; Baquie M; Dai C; Powers AC; Kerr-Conte J; Pattou F; MacDonald RJ; Ferrer J; Wollheim CB. 2009. PDX1 deficiency causes mitochondrial dysfunction and defective insulin secretion through TFAM suppression. Cell Metab 10(2):110-8. [PubMed: 19656489]  [MGI Ref ID J:151308]

Hale MA; Kagami H; Shi L; Holland AM; Elsasser HP; Hammer RE; MacDonald RJ. 2005. The homeodomain protein PDX1 is required at mid-pancreatic development for the formation of the exocrine pancreas. Dev Biol 286(1):225-37. [PubMed: 16126192]  [MGI Ref ID J:103522]

Holland AM; Gonez LJ; Naselli G; Macdonald RJ; Harrison LC. 2005. Conditional expression demonstrates the role of the homeodomain transcription factor Pdx1 in maintenance and regeneration of beta-cells in the adult pancreas. Diabetes 54(9):2586-95. [PubMed: 16123346]  [MGI Ref ID J:101742]

Nishimura W; Bonner-Weir S; Sharma A. 2009. Expression of MafA in pancreatic progenitors is detrimental for pancreatic development. Dev Biol 333(1):108-20. [PubMed: 19576197]  [MGI Ref ID J:152238]

Rulifson IC; Karnik SK; Heiser PW; ten Berge D; Chen H; Gu X; Taketo MM; Nusse R; Hebrok M; Kim SK. 2007. Wnt signaling regulates pancreatic beta cell proliferation. Proc Natl Acad Sci U S A 104(15):6247-52. [PubMed: 17404238]  [MGI Ref ID J:143020]

Spence JR; Lange AW; Lin SC; Kaestner KH; Lowy AM; Kim I; Whitsett JA; Wells JM. 2009. Sox17 regulates organ lineage segregation of ventral foregut progenitor cells. Dev Cell 17(1):62-74. [PubMed: 19619492]  [MGI Ref ID J:151981]

Stanger BZ; Datar R; Murtaugh LC; Melton DA. 2005. Direct regulation of intestinal fate by Notch. Proc Natl Acad Sci U S A 102(35):12443-8. [PubMed: 16107537]  [MGI Ref ID J:101154]

Stanger BZ; Tanaka AJ; Melton DA. 2007. Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver. Nature 445(7130):886-91. [PubMed: 17259975]  [MGI Ref ID J:118596]

Wang S; Hecksher-Sorensen J; Xu Y; Zhao A; Dor Y; Rosenberg L; Serup P; Gu G. 2008. Myt1 and Ngn3 form a feed-forward expression loop to promote endocrine islet cell differentiation. Dev Biol 317(2):531-40. [PubMed: 18394599]  [MGI Ref ID J:136131]

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

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice are maintained as heterozygotes.

Purchasing information

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

Pricing

Supply Details

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes for further information.

Supply Notes

Cryopreserved Embryos This strain is also available as cryopreserved embryos. Orders for cryopreserved embryos may be placed with our Customer Service Department. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos, please visit our Cryopreserved Embryos web page. Cryorecovery - Standard. 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. The total number of animals provided, their gender and genotype will vary. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 13 and 16 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. IMPORTANT NOTE: 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. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location). This strain is included in the Induced Mutant Resource Colony collection. Genomic DNA is available for this strain from the Mouse DNA Resource.

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.

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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.

See Terms of Use tab for General Terms and Conditions

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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Terms of Use

Terms of Use

General Terms and Conditions

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For additional Licensing and Use Restrictions view the link(s) below:
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