B6C3Fe a/a-Qki^qk-v/J

Stock number: 000506
Product name: quaking viable
Strain synonyms: quaking
Research areas: Apoptosis Research, Cell Biology Research, Neurobiology Research, Reproductive Biology Research, Sensorineural Research

Description

These mice carry a spontaneous mutation at the Qki locus characterized by a rapid tremor that increases during locomotion.

Detailed description

Mice homozygous for the quaking spontaneous mutation (qk-v) have marked rapid tremor which disappears when they are at rest but increases during locomotion. The tremor in homozygous mutant mice begins at about 10 days and is fully developed by 3 weeks. Mature mice may have seizures in which a motionless posture is maintained for many seconds. Females are viable and fertile, males are sterile due to defective spermatic differentiation. The entire CNS of quaking mutant mice is severely deficient in myelin and there is a less severe myelin deficiency in the PNS.

Development

The quaking (also called quaking viable) mutation arose spontaneously in 1961 in the DBA/2J strain. It was crossed twice to C3H then transferred to the C57BL/6JEi background via backcross-intercross mating until N10 then sibling bred. At N11F10 it was bred to C57BL/6J-T^2J, and a repulsion stock was generated. In 1976 a Qki^qk-v homozygote was outcrossed to a B6C3HF1 male, removing the T^2J mutation, and the Qki^qk-v mutation was maintained via cross-intercross using Qki^qk-v homozygous females and B6C3F1 males for the cross since homozygous males are sterile. At N8F4 a change was made to use B6C3Fe-a/a F1 for the outcross. In 1987 homozygous females at N15F1 were bred with B6C3F3-a/a F1 males to generate embryos for cryopreservation.

Allele

Symbol: a
Name: nonagouti
MGI accession ID: MGI:1855937
Generation method: Spontaneous
Marker symbol: a
Marker name: nonagouti
Marker synonyms: agouti; agouti signal protein; AGSW; AGTI; AGTIL; As; ASP; SHEP9
Chromosome: 2
Strain of origin: old mutant of the mouse fancy
Molecular note: Characterization of this allele shows an insertion of DNA comprised of a 5.5kb virus-like element, VL30, into the first intron of the agouti gene. The VL30 element itself contains an additional 5.5 kb sequence, flanked by 526 bp of direct repeats (beta4 retroviral sequence). The host integration site is the same as for a^t-2Gso and A^w-38J and includes a duplication of four nucleotides of host DNA and a deletion of 2 bp from the end of each repeat. Northern analysis of mRNA from skin of homozygotes shows a smaller agouti message and levels 8 fold lower than found in wild-type.
General note: Insertion of the LV30 retrotransposon without the beta4 retrovirus sequence does not cause the nonagouti phenotype. J:278039

Allele

Symbol: Qki^qk-v
Name: quaking viable
MGI accession ID: MGI:1856539
Generation method: Spontaneous
Synonyms: qk; Qk^qk; qk^v
Marker symbol: Qki
Marker name: quaking, KH domain containing RNA binding
Marker synonyms: 1110003F05Rik; Hqk; hqkI; l(17)-1Wis; l17Wis1; Qk; QK1; QK3; QkI
Chromosome: 17
Strain of origin: DBA/2J
Molecular note: The quaking phenotype has been attributed to a 1.85 Mb deletion on chromosome 17. The proximal breakpoint was located in the promoter region of the Qk gene and affects transcript levels of that gene. The distal breakpoint lies between exons 5 and 6 of the parkin gene. Both the parkin gene and another co-regulated gene, Pacrg, are inactivated. Although parkin is not expressed in these mutants, the described phenotype appears due to to the defect in Qk expression.
General note: The quaking mutation arose spontaneously in the DBA/2J strain. Homozygotes have marked rapid tremor which disappears when they are at rest but increases during locomotion. It begins at about 10 days and is fully developed by 3 weeks. Mature mice may have seizures in which a motionless posture is maintained for many seconds. Females are viable and fertile, males sterile. Homozygotes are severely deficient in myelin, the material which ensheathes and insulates the axons of the central (CNS) and peripheral (PNS) nervous systems (see Mbp). The entire CNS is very deficient in myelin at all ages (J:13141), and there is a less severe myelin deficiency in the PNS nervous system (J:5177). Myelin sheaths are present in the CNS, but they are thinner than normal, some consisting of only one to four myelin lamellae. The sheaths are usually loosely wound, with patches of oligodendroglial cell cytoplasm between the lamellae, and there are abnormal inclusions and vacuoles in the processes and perikarya of oligodendrocytes. Development of the myelin sheaths appears to be arrested in a stage characteristic of very young animals (J:5189)(J:5271)(J:5218). There is variable hyperplasia of oligodendrocytes, greatest in the tracts with the greatest degree of myelination (J:5615). Axons have normal morphology but there is abnormally high proteolysis in the axons of the optic nerve (J:6971). There is evidence that the myelination defect in the CNS is due to defective oligodendrocytes (J:6216). Handling-induced convulsive seizures in qk/qk mice can be inhibited by administration of N-methyl-D-aspartate (NMDA) antagonists. Modulatory mechanisms for the NMDA receptor complex may differ in qk/qk mice from wild-type (J:1930). a2-adrenoceptor (A2A) antagonists also inhibit these seizures, while A2A agonists potentiate them. qk/qk mice have increased brain binding sites for A2A agonists (J:1169). In the PNS, thinly myelinated and unmyelinated fibers have been described in the sciatic nerve and in the intracranial portion of the trigeminal nerve (J:5189)(J:5271). The sheaths may be structurally abnormal with regions of uncompacted myelin lamellae similar to those of the CNS (J:5778). Orthotopic transplantation of pieces of sciatic nerve between quaking and normal mice has shown that the genetic defect is expressed in Schwann cells (J:14892). Qk causes defective myelinogenesis in both oligodendrocytes and Schwann cells (J:6411). There is an extensive literature on biochemical defects related to the deficiency of myelin in quaking mice (J:26986), a consistent finding of which is a severe deficiency of the myelin lipids, sphingomyelin, cerebrosides, and sulfatides, particularly those containing long-chain fatty acids. The normal increase in these fatty acids which occurs between 15 and 20 days does not occur in qk/qk mice, so that adult mutants tend to resemble very young controls (J:5171). Brain proteolipids in adult quaking mice retain the relative proportions found in 10-day controls (J:5408). The myelin-associated glycoproteins of different molecular weight in the brains of quaking mice 15 days of age and older are expressed in abnormal proportions (J:7990). Synthesis of myelin basic protein and proteolipids is normal in quaking brains but their incorporation into myelin is defective (J:6151). mRNAs for myelin basic protein, for example, occur in oligodendrocyte cell bodies, but not in the cell processes that actually form the myelin sheath, in qk/qk brain (J:1931). Quaking mice may have abnormal levels of copper and zinc in the brain, but the evidence on this point is conflicting (J:7214). The sterility of male qk/qk mice is due to defective spermatid differentiation, the details of which have been described (J:5241). It has been further demonstrated that male sterility in these mice is the result of the loss of Pacrg expression (J:90667).