B6;129S7-Cyp46a1^tm1Rus/J

Stock number: 017759
Research areas: Cardiovascular Research, Metabolism Research, Neurobiology Research, Research Tools

Description

Expression of Cyp46a1 is disrupted in this tau-β-lacZ fusion protein knockin strain. These mice may be useful for studying cholesterol turnover in brain tissues.

Detailed description

A tau-β-galactosidase (lacZ) fusion protein, followed by a neomycin (neo) resistance cassette, replaces the 3' end of exon 1 of the Cyp46a1 gene, abolishing gene function. Cyp46a1 encodes the enzyme cholesterol 24-hydroxylase which is expressed mainly in the brain, with low expression in liver. Cholesterol 24-hydroxylase is involved in cholesterol biosynthesis and turnover, and has also been implicated in the development of amyloid plaques in Alzheimer's disease. Homozygous mice are viable and fertile. In these mice, lacZ staining is evident in the spinal cord, midbrain, and hindbrain at E11.5, with expression decreasing between E11.5 and E13.5. LacZ staining is intensified between E11.5 and E13.5 in cells of the telencephalon, and the cerebral cortex. Beginning at E13.5, expression is restricted to dividing neurons in the neuroepithelium and post-mitotic neurons of the primordial plexiform layer of the telencephalon. These mice display a 40% reduction of new cholesterol synthesis in the brain, while maintaining cholesterol homeostasis in the central nervous system.

Development

A targeting vector was designed to replace the 3' end of exon 1 of the cytochrome P450, family 46, subfamily a, polypeptide 1 (Cyp46a1) gene with a tau-β-galactosidase (lacZ) fusion protein and a neomycin (neo) resistance cassette. The construct was electroporated into 129S7/SvEvBrd-Hprt⁺-derived AB-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts and the resulting chimeric males were bred to C57BL/6J females. These mice were maintained on a mixed background.

Allele

Symbol: Cyp46a1^tm1Rus
Name: targeted mutation 1, David W Russell
MGI accession ID: MGI:2667348
Generation method: Targeted
Attributes: Reporter; Null/Knockout
Marker symbol: Cyp46a1
Marker name: cytochrome P450, family 46, subfamily a, polypeptide 1
Chromosome: 12
Strain of origin: 129S7/SvEvBrd-Hprt⁺
Expressed genes: lacZ,beta-galactosidase,E. coli
Site of expression: lacZ is expressed throughout the brain.
Molecular note: The 3 prime portion of exon 1 as well as a small part of intron 1 were replaced with DNA sequence encoding the N terminus of the bovine tau protein fused to the lacZ gene. mRNA for the targeted gene and its protein were undetectable in the brain of homozygous mice and were reduced in heterozygotes.