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Type Targeted Mutation; Species laboratory mouse Generation ?+F2p Donating Investigator Oksana Lockridge, Eppley Inst. (Univ of Nebraska Med Cntr) Description
Homozygous mice have 25% fetal mortality. Those born have retarded growth, fine motor tremors, unusual posture and gait, no righting reflex, malformed pinna, and sealed eyelids. These mice die emaciated and dehydrated by 3 weeks of age. Enriched diets for the nursing female and pups allow homozygous mice to survive to adulthood. Males exhibit no breeding behavior. Homozygous females can become pregnant when bred to heterozygous or wildtype males, but both female and pups do not survive. Acetylcholinesterase (AChE) activity is completely abrogated in serum and tissue from homozygous mice, and approximately half in heterozygotes. Many symptoms of organophosphate poisoning are observed in homozygous mice, including pulsating paws, body tremor, abnormal gait, pinpoint pupils, muscle weakness, and early death following seizure. When restrained, a white mucus forms on the eyes and seizures may occur. Mice also have several developmental delays, low body mass, decreased pain response, sexual dysfunction, an inability to chew solid food, and a lack of aggression. Homozygous mice are hypersensitive to organophosphates and bambuterol. Respiratory motorneurons are protected from the tonic activity induced by cholinergic agonists. Similarly, homozygous mice have drastic reduction of the M1, M2, and M4 muscarinic acetylcholine receptors in the cortex and hippocampus with decreased cell surface localization and increased intracellular localization of these receptors. Homozygous mice have defective formation of the inner retina associated with apoptotic photoreceptor degeneration with age. Heterozygous mice are viable and fertile with normal maturation and development. They exhibit intermediate sensitivity to organophosphates and are unaffected by bambuterol. This mouse may be useful in studies of toxicology, neuromuscular junctions, nervous system function, neuropsychiatric diseases (Alzheimer's and Parkinson's), and blinding diseases (Retinitis pigmentosa and age-related macular degeneration).The donating investigator has multiple strains available that may be useful for testing toxic compounds, including the AChE-deficient (Stock No. 005987), G117H BChE transgenic (Stock No. 007577), and BChE-deficient (see Stock No. 008077 and Stock No. 008087) mice.
Development
A targeting vector was designed to replace exons 2-5 of the endogenous gene with a neomycin resistance gene. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells (line 3D6) were injected into C57BL/6 blastocysts. The resulting chimeric males were bred to 129S6/SvEvTac females. Heterozygous pups were bred to 129S6/SvEvTac for more than 10 generations before arrival at The Jackson Laboratory.
| Control | ||
|---|---|---|
| Wild-type from the colony | ||
| Considerations for Choosing Controls | ||
Visit the Alzheimer's Disease Mouse Model Resource site for helpful information on Alzheimer's Disease and research resources.
Mammalian Phenotype Terms assigned by genotype
Achetm1Loc/Achetm1Loc
involves: 129S1/Sv * 129S6/SvEvTac * 129X1/SvJ
- lethality-prenatal/perinatal
- prenatal lethality (MGI Ref ID J:76453)
- lethality-postnatal
- postnatal lethality (MGI Ref ID J:76453)
- pups die during the postnatal period between P13-21; none survive beyond 21 days
- growth/size phenotype
- decreased body weight (MGI Ref ID J:76453)
- weight is lower than wild-type from P2 onward, with a clear difference noted at 7 days after birth; weights decreased 1-2 days prior to death at ~P14
- behavior/neurological phenotype
- abnormal gait (MGI Ref ID J:76453)
- null mice are born at frequency of 20% instead of expected 25%
- abnormal posture (MGI Ref ID J:76453)
- splayed feet and legs
- circling (MGI Ref ID J:76453)
- null mice exhibit continuous circling movement upon separation from the nest
- impaired righting response (MGI Ref ID J:76453)
- no righting reflex develops even by 21 days of age, whereas wild-type controls show reflex by 8 days of age
- tremors (MGI Ref ID J:76453)
- fine motor tremor observed at 3-4 days of age
- nervous system phenotype
- abnormal cerebrum morphology (MGI Ref ID J:76453)
- cerebral hemispheres are transulucent in 12-day old mice, whereas they are opaque in wild-type littermates
- hearing/vestibular/ear phenotype
- circling (MGI Ref ID J:76453)
- null mice exhibit continuous circling movement upon separation from the nest
- delayed ear emergence (MGI Ref ID J:76453)
- lack of maturation of the ear structure
- vision/eye phenotype
- eyelids fail to open (MGI Ref ID J:76453)
- failure of eyelids to open; sealed even on P21, while littermates open on P8 to 12
- craniofacial phenotype
- delayed ear emergence (MGI Ref ID J:76453)
- lack of maturation of the ear structure
Research Applications
This mouse can be used to support research in many areas including:
Developmental Biology Research
Embryonic Lethality (Homozygous) (incomplete)
Neurodevelopmental Defects
Perinatal Lethality (Homozygous)
Neurobiology Research
Alzheimer's Disease
Neurodevelopmental Defects
Neuromuscular Defects
Neurotransmitter Receptor and Synaptic Vesicle Defects
Parkinson's Disease
Tremor Defects
Research Tools
Sensorineural Research (retinal degeneration)
Toxicology Research (drug metabolism)
Toxicology Research (drug/compound testing)
Sensorineural Research
Retinal Degeneration
| Allele Symbol | Achetm1Loc | ||
|---|---|---|---|
| Allele Name | targeted mutation 1, Oksana Lockridge | ||
| Common Name(s) | AChE ko; AChE-; | ||
| 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<+> | ||
| Gene Symbol and Name | Ache, acetylcholinesterase | ||
| Chromosome | 5 | ||
| Gene Common Name(s) | ARACHE; N-ACHE; YT; | ||
| Molecular Note | A 5 kb genomic fragment containing exons 2-5 was replaced by a neomycin resistance gene cassette. Enzymatic activity assays on blood serum derived from homozygous mice confirmed that no functional protein was made from this allele. [MGI Ref ID J:56242] | ||
Genotyping Protocols
Achetm1Loc, STD PCR, vers. 1
Helpful Links
Optimizing PCR Protocols
Xie W; Wilder PJ; Stribley J; Chatonnet A; Rizzino A; Taylor P; Hinrichs SH; Lockridge O. 1999. Knockout of one acetylcholinesterase allele in the mouse. Chem Biol Interact 119-120:289-99. [PubMed: 10421464] [MGI Ref ID J:56242]
Achetm1Loc related
Bytyqi AH; Lockridge O; Duysen E; Wang Y; Wolfrum U; Layer PG. 2004. Impaired formation of the inner retina in an AChE knockout mouse results in degeneration of all photoreceptors. Eur J Neurosci 20(11):2953-62. [PubMed: 15579149] [MGI Ref ID J:101277]Chatonnet F; Boudinot E; Chatonnet A; Taysse L; Daulon S; Champagnat J; Foutz AS. 2003. Respiratory survival mechanisms in acetylcholinesterase knockout mouse. Eur J Neurosci 18(6):1419-27. [PubMed: 14511322] [MGI Ref ID J:89715]
Cousin X; Strahle U; Chatonnet A. 2005. Are there non-catalytic functions of acetylcholinesterases? Lessons from mutant animal models. Bioessays 27(2):189-200. [PubMed: 15666354] [MGI Ref ID J:95975]
Duysen EG; Li B; Darvesh S; Lockridge O. 2007. Sensitivity of butyrylcholinesterase knockout mice to (--)-huperzine A and donepezil suggests humans with butyrylcholinesterase deficiency may not tolerate these Alzheimer's disease drugs and indicates butyrylcholinesterase function in neurotransmission. Toxicology 233(1-3):60-9. [PubMed: 17194517] [MGI Ref ID J:130048]
Duysen EG; Li B; Xie W; Schopfer LM; Anderson RS; Broomfield CA; Lockridge O. 2001. Evidence for nonacetylcholinesterase targets of organophosphorus nerve agent: supersensitivity of acetylcholinesterase knockout mouse to VX lethality J Pharmacol Exp Ther 299(2):528-35. [PubMed: 11602663] [MGI Ref ID J:103438]
Duysen EG; Stribley JA; Fry DL; Hinrichs SH; Lockridge O. 2002. Rescue of the acetylcholinesterase knockout mouse by feeding a liquid diet; phenotype of the adult acetylcholinesterase deficient mouse. Brain Res Dev Brain Res 137(1):43-54. [PubMed: 12128253] [MGI Ref ID J:78335]
Li B; Duysen EG; Volpicelli-Daley LA; Levey AI; Lockridge O. 2003. Regulation of muscarinic acetylcholine receptor function in acetylcholinesterase knockout mice. Pharmacol Biochem Behav 74(4):977-86. [PubMed: 12667913] [MGI Ref ID J:102434]
Li B; Stribley JA; Ticu A; Xie W; Schopfer LM; Hammond P; Brimijoin S; Hinrichs SH; Lockridge O. 2000. Abundant tissue butyrylcholinesterase and its possible function in the acetylcholinesterase knockout mouse. J Neurochem 75(3):1320-31. [PubMed: 10936216] [MGI Ref ID J:64025]
Mesulam MM; Guillozet A; Shaw P; Levey A; Duysen EG; Lockridge O. 2002. Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine. Neuroscience 110(4):627-39. [PubMed: 11934471] [MGI Ref ID J:126281]
Mouisel E; Blondet B; Escourrou P; Chatonnet A; Molgo J; Ferry A. 2006. Outcome of acetylcholinesterase deficiency for neuromuscular functioning. Neurosci Res 55(4):389-96. [PubMed: 16766072] [MGI Ref ID J:112809]
Volpicelli-Daley LA; Hrabovska A; Duysen EG; Ferguson SM; Blakely RD; Lockridge O; Levey AI. 2003. Altered striatal function and muscarinic cholinergic receptors in acetylcholinesterase knockout mice Mol Pharmacol 64(6):1309-16. [PubMed: 14645660] [MGI Ref ID J:103439]
Xie W; Stribley JA; Chatonnet A; Wilder PJ; Rizzino A; McComb RD; Taylor P; Hinrichs SH; Lockridge O. 2000. Postnatal developmental delay and supersensitivity to organophosphate in gene-targeted mice lacking acetylcholinesterase. J Pharmacol Exp Ther 293(3):896-902. [PubMed: 10869390] [MGI Ref ID J:76453]
Colony Maintenance
Breeding & Husbandry When maintaining a live colony, heterozygous mice are bred with wild type siblings. Homozygous mice do not produce litters. If adult homozygous mice are to be generated, the donating investigator recommends that heterozygous dams are given a high fat diet while gestating and nursing. Homozygous mice should be weaned at day 15 and given a nutrient rich liquid diet. Incisor trimming may be needed for liquid fed mice (Ensure from Abbott Labs). Homozygous mice have improper urination and defecation habits in the nest.
*Price(s) in US dollars ($)
Weeks of Age Price* Gender Cryorecovery Fee $1900.00
| Standard Supply | Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information. |
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| Supply Notes |
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*Price(s) in US dollars ($)
Weeks of Age Price* Gender Cryorecovery Fee $2470.00
| Standard Supply | Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information. |
|---|---|
| Supply Notes |
|
| 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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