Description

Strain Information

Type Mutant Stock; Targeted Mutation; Mating System +/+ sibling x Heterozygote         (Female x Male) Species laboratory mouse Generation F?+ (24-SEP-08)   Donating Investigator Mulchand Patel,   SUNY at Buffalo

Description
Mice heterozygous for the Dld (dihydrolipoamide dehydrogenase or E3 component) targeted mutation are viable and fertile. Heterozygous mice exhibit approximately half of wild-type enzymatic activity levels for E3 and all affected mitochondrial multienzyme complexes. Heterozygotes (on a C57BL/6;129P2 genetic background) exhibit increased vulnerability to treatments with MPTP (dopaminergic neurotoxin used to induce Parkinson's disease-like lesions), malonate (inhibitor of cellular respiration used to mimic Huntington's disease features), and 3-NP (mitochondrial toxin used to mimic Huntington's disease features). Homozygous mice exhibit normal development and metabolism during the preimplantation period, explained by the persistence of E3 enzyme from the oocyte. Homozygotes exhibit developmental delays shortly after implantation (7.5 to 8.5 days postcoitum (dpc)) and cease development within the subsequent 2 days. These Dld mutant mice may be useful to study early murine embryonic metabolism, including glucose and mitochondrial metabolism during the early postimplantation period. As altered energy metabolism and reductions in alpha-ketoacid dehydrogenase complexes have also been associated with many neurodegenerative disorders, these mice may also be useful for studying Parkinson's disease, Huntington's disease, and/or Alzheimer's disease. Because the metabolic disturbances associated with E3 deficiency (Dld deficiency) cause a variant of Maple Syrup Urine Disease (MSUD) in which there is an accompanying lactic acidosis due to concomitant deficiency of pyruvate dehydrogenase complex, these mice may be useful in such studies or in conjunction with iMSUD mice (Stock No. 006999).

Development
A targeting vector was designed to insert a beta actin promoter-driven neomycin phosphotransferase gene (lacking a polyA signal) into exon 10 of the targeted gene. The construct was electroporated into 129P2/OlaHsd-derived E14.1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and chimeric males were bred with C57BL/6 females to produce heterozygous mutant mice. These heterozygotes were subjected to an additional round of breeding with C57BL/6J inbred mice, and then maintained by interbreeding of heterozygous animals for many generations prior to arrival at The Jackson Laboratory. Upon arrival, mutant mice were bred to C57BL/6J for at least one generation to establish the colony.

Control Information

	Control
	Wild-type from the colony
	100492 B6129PF1/J	(approximate)
Considerations for Choosing Controls

Additional Web Information

Visit the Alzheimer's Disease Mouse Model Resource site for helpful information on Alzheimer's Disease and research resources.

Phenotype

Phenotype Information

Mammalian Phenotype Terms assigned by genotype

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

Dld^tm1Ptl/Dld^tm1Ptl

        involves: 129P2/OlaHsd * Black Swiss

• lethality-prenatal/perinatal
• embryonic lethality before turning of embryo (MGI Ref ID J:45074)
  • homozygous null embryos exhibit peri-gastrulation lethality and are resorbed by 9.5 dpc
• embryogenesis phenotype
• abnormal endoderm development (MGI Ref ID J:45074)
  • at 7.5 dpc, the mutant visceral endoderm appears to proliferate relatively longer and forms a thickened columnar layer instead of the unicellular flat squamous layer found in wild-type
• embryonic growth arrest (MGI Ref ID J:45074)
  • homozygous null embryos display a developmental cessation at the onset of gastrulation
  • no mutant embryos develop normally to 8.5 dpc
• embryonic growth retardation (MGI Ref ID J:45074)
  • homozygous null embryos display a developmental delay at 7.5 dpc
  • at 7.5 dpc, mutant embryos resemble 6.5-dpc wild-type egg cylinders in size and proportion
• reduced embryo size (MGI Ref ID J:45074)
  • at 7.5 dpc, mutant embryos are noticeably smaller than wild-type embryos
• growth/size phenotype
• embryonic growth retardation (MGI Ref ID J:45074)
  • homozygous null embryos display a developmental delay at 7.5 dpc
  • at 7.5 dpc, mutant embryos resemble 6.5-dpc wild-type egg cylinders in size and proportion
• reduced embryo size (MGI Ref ID J:45074)
  • at 7.5 dpc, mutant embryos are noticeably smaller than wild-type embryos

Research Applications

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

Developmental Biology Research
Embryonic Lethality (Homozygous)

Metabolism Research
Enzyme Deficiency
Free Radical Research

Neurobiology Research
Alzheimer's Disease
Huntington's disease
Metabolic Defects
Neurodegeneration
Parkinson's Disease (increased vulnerability to MPTP)

Research Tools
Developmental Biology Research
Metabolism Research
Neurobiology Research

Genes & Alleles

Gene & Allele Information

Allele Symbol		Dldtm1Ptl
Allele Name		targeted mutation 1, Mulchand S Patel
Common Name(s)		Dld-/-; Dldtm1mjp;
Mutation Made By		Mark Johnson,   Case Western Reserve University
Strain of Origin		129P2/OlaHsd
ES Cell Line Name		E14.1
ES Cell Line Strain		129P2/OlaHsd
Gene Symbol and Name		Dld, dihydrolipoamide dehydrogenase
Chromosome		12
Gene Common Name(s)		AI315664; AI746344; DLDH; E3; GCSL; LAD; PHE3; branched chain alpha-keto acid dehydrogenase complex subunit E3; dihydrolipoyl dehydrogenase; expressed sequence AI315664; expressed sequence AI746344;
Molecular Note		Exon 10 was disrupted by the insertion of a neomycin selection cassette. Northern blot analysis of total hepatic and renal RNA showed that transcript levels are reduced by approximately 50% in heterozygous mice. RT-PCR analysis confirmed that the neo transgene was not excised via an altered splicing pattern. [MGI Ref ID J:45074]

Genotyping

Genotyping Information

Genotyping Protocols

Dld^tm1Ptl, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Johnson MT; Yang HS; Magnuson T; Patel MS. 1997. Targeted disruption of the murine dihydrolipoamide dehydrogenase gene (Dld) results in perigastrulation lethality. Proc Natl Acad Sci U S A 94(26):14512-7. [PubMed: 9405644]  [MGI Ref ID J:45074]

Klivenyi P; Starkov AA; Calingasan NY; Gardian G; Browne SE; Yang L; Bubber P; Gibson GE; Patel MS; Beal MF. 2004. Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3-nitropropionic acid neurotoxicity. J Neurochem 88(6):1352-60. [PubMed: 15009635]  [MGI Ref ID J:107994]

Starkov AA; Fiskum G; Chinopoulos C; Lorenzo BJ; Browne SE; Patel MS; Beal MF. 2004. Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci 24(36):7779-88. [PubMed: 15356189]  [MGI Ref ID J:133657]

Additional References

Dld^tm1Ptl related

Calingasan NY; Ho DJ; Wille EJ; Campagna MV; Ruan J; Dumont M; Yang L; Shi Q; Gibson GE; Beal MF. 2008. Influence of mitochondrial enzyme deficiency on adult neurogenesis in mouse models of neurodegenerative diseases. Neuroscience 153(4):986-96. [PubMed: 18423880]  [MGI Ref ID J:139376]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, heterozygous mice may be bred. Homozygous mice die in utero.
Diet Information	LabDiet® 5K52/5K67

Purchasing information

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

 

This strain is currently Under Development for Distribution Colony.
To register your interest in this strain go to the Strain Interest Form.

Estimated Available for Sale Date: 20-OCT-08

Please note: Estimated available for sale dates are provided to keep customers better informed on strains under development. Please note that our Colony Managers routinely monitor the target date and edit it based on breeding performance and other factors. The length of time it takes to make a new strain available for sale depends on genotype, age, number of animals sent by the Donating Investigator, breeding performance, additional strain development (backcrossing, making homozygous), and anticipated demand for the strain/interest registered.

View All Strains Under Development

Pricing

Control Information

	Control
	Wild-type from the colony
	100492 B6129PF1/J	(approximate)
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

View JAX^® Mice & Services Conditions of Use.

Use restrictions apply, see Policy on Licensing and Use Restrictions.

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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