B6.129P2-Ace2^tm1Pngr/J

Stock number: 035518
Product name: ace2^-
Research areas: Cardiovascular Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Research Tools, Virology Research

Description

Ace2 knock-out (KO) mice contain a neomycin cassette designed to replace exon 9 of the Ace2 (angiotensin I converting enzyme (peptidyl-dipeptidase A) 2) gene. Ace2 is the receptor used for cellular entry by several coronaviruses, including severe acute respiratory syndrome coronavirus-1 (SARS-CoV) and -2 (SARS-CoV-2). Homozygous females and hemizygous males exhibit decreased susceptibility to severe acute respiratory syndrome coronavirus (SARS-CoV) infection. This strain may be useful for the study of 2019 novel coronavirus (SARS-CoV-2) pathogenesis as well as cardiovascular disease.

Detailed description

Please note, these mice should be handled in a manner consistent with CDC/ABSA/WHO guidelines for prevention of human infection with the SARS-CoV-2 virus. Proper PPE and handling methods should be used at all times when working with these mice. Additional important guidelines for using SARS-CoV-2 susceptible mouse lines.

Ace2 (angiotensin I converting enzyme (peptidyl-dipeptidase A) 2) encodes a dipeptidyl carboxydipeptidase that functions to catalyze cleavage of angiotensin I and II. Human ACE2 is the receptor used for cellular entry by several coronaviruses, including severe acute respiratory syndrome coronavirus-1 (SARS-CoV), severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2; 2019 novel coronavirus) and HCoV-NL63. Ace2 knock-out (KO) mice contain a neomycin cassette designed to replace exon 9. Mice homozygous (or hemizygous) for the mutation are viable and fertile. Homozygous females and hemizygous males infected with SARS-CoV (Beijing strain, PUMC01 isolate) via intranasal inoculation develop decreased viral titers in the lungs, decreased leukocyte infiltrates, reduced pathologic alterations in the lung as compared to wild type mice. Alternatively, infection with H5N1 avian flu virus results in increased susceptibility (higher viral titers, increased mortality and lung inflammation/edema). Ace2 KO females and hemizygous males also exhibit a reduction in cardiac contractility, although the phenotype is dependent on genetic background and is more severe in males. Multiple other pathologies have been reported to depend on ACE2 expression, including liver and lung fibrosis, bleomycin-induced lung injury, or diabetic nephropathy. This strain may be useful for the study of 2019 novel coronavirus (SARS-CoV-2) pathogenesis as well as cardiovascular, fibrotic, or diabetic disease.

Development

A targeting vector containing a neomycin resistance cassette (in anti-sense orientation) was used to replace exon 9 (+1069 to +1299) of the Ace2 gene on the X Chromosome. The construct was electroporated into 129P2/OlaHsd-derived E14K embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were crossed to C57BL/6 females, and offspring were backcrossed to C57BL/6 for at least 10 generations. Western blot analysis in kidneys demonstrates the absence of protein. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).

Allele

Symbol: Ace2^tm1Pngr
Name: targeted mutation 1, Josef M Penninger
MGI accession ID: MGI:2661723
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Ace2
Marker name: angiotensin I converting enzyme (peptidyl-dipeptidase A) 2
Marker synonyms: 2010305L05Rik; ACEH
Chromosome: X
Strain of origin: 129P2/OlaHsd
Molecular note: Exon 9 was replaced with a neomycin selection cassette inserted by homologous recombination. The deleted region (nt 1069 through 1299) encoded the zinc binding catalytic domain. Northern and Western blot analyses indicated that neither transcript nor protein are produced by the mutant allele.