B6;129P2-Dld^tm1Ptl/J

Stock number: 008333
Research areas: Developmental Biology Research, Metabolism Research, Neurobiology Research, Research Tools

Description

These Dld (dihydrolipoamide dehydrogenase or E3 component) 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 in studies related to 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).

Detailed 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 two 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.

Allele

Symbol: Dld^tm1Ptl
Name: targeted mutation 1, Mulchand S Patel
MGI accession ID: MGI:2182403
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: Dld^-; Dld^tm1mjp
Marker symbol: Dld
Marker name: dihydrolipoamide dehydrogenase
Marker synonyms: branched chain alpha-keto acid dehydrogenase complex subunit E3; dihydrolipoyl dehydrogenase; DLDD; DLDH; E3; GCSL; LAD; OGDC-E3; PHE3
Chromosome: 12
Strain of origin: 129P2/OlaHsd
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.