JAX Mouse Strain Datasheet - 005701

STOCK Pdx1^tm1Macd/J

Stock No:: 005701 |; Pdx1^tTA KI

Targeted Mutation

Cryo Recovery

Overview

Also Known As: Pdx1^tTA KI

These knock-in mice express a transactivator protein (tTA) from the endogenous promoter/enhancer elements of the Pdx1 gene in the pancreas.

Donating Investigator

Raymond MacDonald, UTSW Medical Center

Genetic overview

Genetic Background	Generation

Pdx1^tm1Macd

Allele Type	Gene Symbol	Gene Name
Targeted (Transactivator)	Pdx1	pancreatic and duodenal homeobox 1

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Research Applications

Endocrine Deficiency Research
Metabolism Research
Research Tools

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Base Price

Starting at:

$2,595.00 Domestic price Cryo Recovery

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Details

Detailed 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.

Expression Data

Expressed Gene	tTA, tetracycline-controlled transactivator, E. coli
Site of Expression	Expresses tTA in pancreas.

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Selected References

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: J:79206

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Genetics

Pdx1^tm1Macd

Allele Symbol: Pdx1^tm1Macd

Allele Name	targeted mutation 1, Raymond J MacDonald
Allele Type	Targeted (Transactivator)
Allele Synonym(s)	Pdx1^tTA
Gene Symbol and Name	Pdx1, pancreatic and duodenal homeobox 1
Gene Synonym(s)	GSF; IDX-1; IPF-1; IPF1; IUF1; Idx1; Ipf1; Ipf1; MODY4; Mody4; PAGEN1; PDX-1; STF-1; Stf1; insulin promoter factor 1; insulin promoter factor 1, homeodomain transcription factor; pancreatic and duodenal homeobox gene 1; pdx-1
Expressed Gene	tTA, tetracycline-controlled transactivator, E. coli
Site of Expression	Expresses tTA in pancreas.
Strain of Origin	(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Chromosome	5
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.
Mutations Made By	Raymond MacDonald, UTSW Medical Center

Disease/Phenotype

Disease Terms

Research Areas By Genotype

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
  - Tissue/Cell Markers: multiple
  - Tissue/Cell Markers: pancreatic beta cells
- Tet Expression Systems
  - tTA/rtTA Expressing Strains

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Pdx1^tm1Macd/Pdx1⁺
involves: 129S1/Sv * 129X1/SvJ

homeostasis/metabolism phenotype

impaired glucose tolerance
- heterozygotes display partially impaired early response to glucose challenge compared to wild-type mice; ability to recover after glucose challenge is impaired
- heterozygotes display partially impaired glucose tolerance compared to wild-type mice; doxycycline treatment has no effect

Genotype: Pdx1^tm1Macd/Pdx1^tm1Macd
involves: 129S1/Sv * 129X1/SvJ

liver/biliary system phenotype

liver/biliary system phenotype
- 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

Genotype: 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
- 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

decreased insulin secretion
- 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

impaired glucose tolerance
- 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 diabetescose levels recover to basal levels within 3 hours; by 14 days of doxycycline treatment, mice have diabetes

increased circulating glucose level
- with doxycycline treatment for 21 day, adult rescue mice show a 4-fold increase in fasting blood glucose to diabetic levels

increased glucagon secretion
- in doxycycline-treated mice there is an increase in glucagons-positive cells

endocrine/exocrine gland phenotype

abnormal pancreas development
- 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 tissued with no acinar or islet tissue

abnormal pancreatic beta cell morphology
- after 14 or 28 days of dox treatment there are, still present, beta cells which lack insulin

decreased insulin secretion
- 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
- in doxycycline-treated mice there is an increase in glucagons-positive cells

small pancreatic islets
- after dox treatment for 14 days, there is a significant decrease in islet area compared to wild-type

cellular phenotype

increased cell proliferation
- foci of duct proliferation are present in mice after 14 days of doxycycline treatment and become more prominent with continued treatment

Genotype: 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
- transgenic mice gradually attain an impaired glucose tolerance response to glucose challenge

endocrine/exocrine gland phenotype

abnormal pancreas development
- 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
- 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 aciniters lacking ductal markers which are polarized, arranged around a central lumen and resemble immature acini
- 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
- 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
- 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

absent pancreas
- ~1/5 pups are born without a pancreas; rescue of pancreas formation is observed in ~80% of transgenic mice

References

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: J:79206

Additional - Pdx1^tm1Macd related

Afelik S; Qu X; Hasrouni E; Bukys MA; Deering T; Nieuwoudt S; Rogers W; Macdonald RJ; Jensen J. 2012. Notch-mediated patterning and cell fate allocation of pancreatic progenitor cells. Development 139(10):1744-53. PubMed: 22461559 MGI: J:184016
Azizoglu DB; Chong DC; Villasenor A; Magenheim J; Barry DM; Lee S; Marty-Santos L; Fu S; Dor Y; Cleaver O. 2016. Vascular development in the vertebrate pancreas. Dev Biol 420(1):67-78. PubMed: 27789228 MGI: J:237925
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: 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: 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: J:103522
Hale MA; Swift GH; Hoang CQ; Deering TG; Masui T; Lee YK; Xue J; MacDonald RJ. 2014. The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis. Development 141(16):3123-33. PubMed: 25063451 MGI: J:214089
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: J:101742
Jonatan D; Spence JR; Method AM; Kofron M; Sinagoga K; Haataja L; Arvan P; Deutsch GH; Wells JM. 2014. Sox17 regulates insulin secretion in the normal and pathologic mouse beta cell. PLoS One 9(8):e104675. PubMed: 25144761 MGI: J:221088
Magenheim J; Ilovich O; Lazarus A; Klochendler A; Ziv O; Werman R; Hija A; Cleaver O; Mishani E; Keshet E; Dor Y. 2011. Blood vessels restrain pancreas branching, differentiation and growth. Development 138(21):4743-52. PubMed: 21965615 MGI: J:181009
Martin D; Kim YH; Sever D; Mao CA; Haefliger JA; Grapin-Botton A. 2015. REST represses a subset of the pancreatic endocrine differentiation program. Dev Biol 405(2):316-27. PubMed: 26156633 MGI: J:225823
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: J:152238
Qu X; Afelik S; Jensen JN; Bukys MA; Kobberup S; Schmerr M; Xiao F; Nyeng P; Veronica Albertoni M; Grapin-Botton A; Jensen J. 2013. Notch-mediated post-translational control of Ngn3 protein stability regulates pancreatic patterning and cell fate commitment. Dev Biol 376(1):1-12. PubMed: 23370147 MGI: J:195161
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: J:143020
Salem HH; Trojanowski B; Fiedler K; Maier HJ; Schirmbeck R; Wagner M; Boehm BO; Wirth T; Baumann B. 2014. Long-term IKK2/NF-kappaB signaling in pancreatic beta-cells induces immune-mediated diabetes. Diabetes 63(3):960-75. PubMed: 24296718 MGI: J:209076
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: 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: 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: 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: J:136131

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Cryorecovery - Pricing

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Progeny testing is not required

The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. 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. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 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.

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Also Known As: Pdx1tTA KI

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Pdx1tm1Macd

Allele Symbol: Pdx1tm1Macd

Disease Terms

Research Areas By Genotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Pdx1tm1Macd/Pdx1+involves: 129S1/Sv * 129X1/SvJ

homeostasis/metabolism phenotype

Genotype: Pdx1tm1Macd/Pdx1tm1Macdinvolves: 129S1/Sv * 129X1/SvJ

liver/biliary system phenotype

Genotype: Pdx1tm1Macd/Pdx1tm1Macd Tg(tetO-Ipf1,EGFP)956.6Macd/0involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL

homeostasis/metabolism phenotype

endocrine/exocrine gland phenotype

cellular phenotype

Genotype: Pdx1tm1Macd/Pdx1tm1Macd Tg(tetO-Ipf1,lacZ)958.1Macd/0involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL

homeostasis/metabolism phenotype

endocrine/exocrine gland phenotype

References

Additional - Pdx1tm1Macd related

Genotyping Protocols

Breeding Considerations

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Progeny testing is not required

RELATED PRODUCTS AND SERVICES

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Also Known As: Pdx1^tTA KI

Pdx1^tm1Macd

Allele Symbol: Pdx1^tm1Macd

Genotype: Pdx1^tm1Macd/Pdx1⁺
involves: 129S1/Sv * 129X1/SvJ

Genotype: Pdx1^tm1Macd/Pdx1^tm1Macd
involves: 129S1/Sv * 129X1/SvJ

Genotype: Pdx1^tm1Macd/Pdx1^tm1Macd Tg(tetO-Ipf1,EGFP)956.6Macd/0
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL

Genotype: Pdx1^tm1Macd/Pdx1^tm1Macd Tg(tetO-Ipf1,lacZ)958.1Macd/0
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL

Additional - Pdx1^tm1Macd related