B6.129S4-Asgr1^tm1Sau/SaubJxmJ

Stock number: 009105
Research areas: Cardiovascular Research, Developmental Biology Research, Hematological Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Research Tools

Description

These mice harbor a targeted mutation of the asialoglycoprotein receptor 1 locus that abolishes endogenous gene expression. Impaired hepatic clearance of asialoglycoproteins is observed.

Detailed description

These mice harbor a targeted mutation of the asialoglycoprotein receptor 1 (Asgr1; also known as hepatic lectin-1 [HL-1]) locus that abolishes endogenous gene expression. Homozygous mice (Asgr1-/- mice) are viable and fertile, with no plasma asialoglycoprotein or platelet level abnormalities. Asgr1-/- mice have impaired hepatic clearance of asialoglycoproteins (exogenous desialylated glycoproteins). Homozygous mice also exhibit altered von Willebrand factor (vWF) levels (increased plasma vWF and reduced hepatocyte-associated vWF). Asgr1-deficiency is associated with reduced bleeding time and enhanced platelet survival. When injected with Streptococcus pneumoniae, homozygous mice have increased susceptibility to infection and mortality (severe intravascular coagulation due to impaired clearance of prothrombotic components: platelets and vWF desialylated by the bacterium's neuraminidase are not eliminated from circulation). These Asgr1 mutant mice may be useful in studying the function of the hepatocyte Ashwell-Morell asialoglycoprotein receptor and its ligands (asialoglycoproteins, von Willebrand factor (vWF) and platelets) in blood coagulation and thrombosis, as well as the capture and endocytosis of a wide range of exogenously administered, potentially deleterious circulating glycoproteins.

Development

A targeting vector was designed by the laboratory of Dr. Brian Sauer (while at Oklahoma Medical Research Foundation) to delete the MHL-1 major subunit coding region in exon 2 of the asialoglycoprotein receptor 1 (Asgr1; also known as hepatic lectin-1 [HL-1]) locus and insert a loxp-flanked PGKneo cassette (followed by a synthetic lox511 site) two nucleotides before the Asgr1 translational start site. This construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts and chimeric offspring were bred with C57BL/6J mice to generate the mutant colony. These MHL-1 null (or Asgr1 null) mice were backcrossed for at least six generations to C57BL/6J and then sent to Dr. Jamey D. Marth (at University of California San Diego). The donating investigator reported that these Asgr1 null mice were backcrossed to C57BL/6NHsd mice (see SNP note below) for at least six generations. Upon arrival at The Jackson Laboratory Repository, mice were bred to C57BL/6NJ (Stock No. 005304) for at least one generation to establish the colony. During backcrossing, the Y chromosome may not have been fixed to the C57BL/6N genetic background.

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, at least 1 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.

Allele

Symbol: Asgr1^tm1Sau
Name: targeted mutation 1, Brian Sauer
MGI accession ID: MGI:3798982
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Asgr1
Marker name: asialoglycoprotein receptor 1
Chromosome: 11
Strain of origin: 129S4/SvJae
Molecular note: The coding region of exon 2 was replaced with a floxed neo cassette with an additional 3' lox511 site.