B6.129S5-Dhcr24^tm1Lex/SbpaJ

Stock number: 012564
Product name: Dhcr24 KO
Research areas: Cardiovascular Research, Cell Biology Research, Dermatology Research, Developmental Biology Research, Endocrine Deficiency Research, Metabolism Research, Neurobiology Research, Research Tools

Description

These mice harbor a Dhcr24-knockout allele that disrupts catalysis of the last step of cholesterol biosynthesis (the conversion of desmosterol to cholesterol), and may be useful in studying cholesterol biosynthesis, epidermal development, keratinocyte differentiation, and epidermal barrier function, as well as Alzheimer's disease and tumor biology. In addition, the Dhcr24 gene (also called selective Alzheimer's disease indicator-1 (Seladin-1)) is reported to be a liver X receptor (LXR) target gene.

Detailed description

Homozygous mice on the C57BL/6 genetic background die within the first postnatal day with features of lethal restrictive dermopathy; including taut, wrinkle-free, shiny skin, severe defects in epidermal maturation/epidermal barrier function (impaired epidermal development), and increased presence of hyperproliferative immature keratinocytes (defective keratinocyte differentiation). The increased transepidermal water loss/increased epidermal water content is associated with increased aquaporin-3 (AQP3) expression throughout the epidermis. Mice heterozygous for this allele are viable and fertile, with no overt phenotype. As the Dhcr24 protein functions to catalyze the last step of cholesterol biosynthesis (the conversion of desmosterol to cholesterol), homozygous disruption of this locus results in desmosterolosis: almost no cholesterol in plasma and tissues with ~99% of total sterols in the form of desmosterol. lacZ expression from the mutant allele is not characterized.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. It should be noted that the phenotype of Dhcr24-mutant mice was originally described on a mixed C57BL/6;129S5 genetic background. We will modify the strain description if necessary as published results become available.

Development

The Dhcr24 knockout mutation was created by the laboratory of Dr. Elena Feinstein (Quark Biotech). A targeting vector was designed to delete a 249 bp region containing exon 1 of the targeted gene and replace it with a lacZ/neo selection cassette. The construct was electroporated into 129S5/SvEvBrd-derived Lex-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts and chimeric males were bred with albino C57BL/6 females to establish the colony. In ~2004, heterozygous mutant mice (B6;129S5 mixed background) were sent to Dr. Shailendra B. Patel (while at Medical University of South Carolina) where they were backcrossed to C57BL/6J mice for three generations. Dr. Patel moved his colony to Medical College of Wisconsin, and then further bakcrossed the colony to C57BL/6J mice for 11 more generations. Heterozygous mice backcrossed to C57BL/6J for a total of at least 14 generations were sent to The Jackson Laboratory Repository. Upon arrival, mice were bred to C57BL/6J (Stock No. 000664) for at least one generation to establish the colony.

Allele

Symbol: Dhcr24^tm1Lex
Name: targeted mutation 1, Lexicon Genetics
MGI accession ID: MGI:3027024
Generation method: Targeted
Attributes: Reporter; Null/Knockout
Synonyms: Dhcr24-; DHCR24^-; Dhcr24^tm1Fein
Marker symbol: Dhcr24
Marker name: 24-dehydrocholesterol reductase
Marker synonyms: 2310076D10Rik; 3-beta-hydroxysterol delta-24 reductase; 5830417J06Rik; DCE; mKIAA0018; Nbla03646; SELADIN1; seladin-1
Chromosome: 4
Strain of origin: 129S5/SvEvBrd
Expressed genes: lacZ,beta-galactosidase,E. coli
Molecular note: The endogenous locus was disrupted by the insertion of a cassette containing lacZ and neo. Transcript was undetected in homozygous mutant mice by Northern blot analysis of RNA obtained from brain and skin tissue.