B6.Cg(FVB)-Mertk^tm1.1Irb/J

Stock number: 040469
Product name: Mertk^CR
Research areas: Cell Biology Research, Immunology, Inflammation and Autoimmunity Research

Description

Mertk^CR mice had codons 483-488 in exon 10 of the MER proto-oncogene tyrosine kinase (Mertk) gene removed, creating a cleavage resistant (CR) MerTK protein. These mice may be useful for studying MerTK-cleavage and the biosynthesis of specialized proresolving mediators (SPMs) during the resolution response in chronic inflammatory diseases.

Detailed description

Mertk^CR mice have codons 483-488 in exon 10 of the MER proto-oncogene tyrosine kinase (Mertk) gene removed. Mertk encodes a macrophage cell-surface protein that mediates a key process in inflammation resolution, efferocytosis, the process by which phagocytic cells engulf and clear apoptotic cells, preventing tissue damage and inflammation, and promoting tissue repair and homeostasis after acute inflammation.

Under inflammatory conditions the ectodomain of MerTK is cleaved by the metalloproteinase, ADAM17, at proline-485, disabling MerTK. The cleavage product, soluble Mer (sol-Mer), may competitively inhibit the interaction of intact MerTK with its ligands, preventing efferocytosis which can lead to the excessive inflammation and tissue damage found in several chronic inflammatory diseases, including atherosclerosis and neurodegeneration. Plasma sol-Mer is increased in patients with inflammatory diseases such as active systemic lupus erythematosus and rheumatoid arthritis. Cell-surface MerTK is lower in macrophages in ADAM17-rich areas in advanced human atherosclerotic lesions.

Mertk^CR homozygous knock-in mice are mice are viable and fertile. They lack codons 483-488, including proline-485, which leads to the expression of a variant of MerTK that is cleavage resistant (CR). These mice have increased circulating levels of specialized proresolving mediators (SPMs), long-chain fatty acid-derived lipid mediators that act downstream of MerTK to temper inflammation, enhance efferocytosis, and repair tissue damage after inflammation. They also exhibit less lung injury after ischemia–reperfusion (I/R) injury.

MerTK cleavage in liver macrophages decreases during the progression from non-fibrotic hepatosteatosis into fibrotic nonalcoholic steatohepatitis (NASH), and these mice with a cleavage-resistant MerTK mutation have increased NASH fibrosis.

Development

The Mertk^CR targeting vector was designed to delete codons 483-488 in exon 10 of the MER proto-oncogene tyrosine kinase (Mertk) gene, and a loxP flanked neomycin resistance (neo) cassette was inserted downstream of exon 10. The construct was electroporated into (C57BL/6J x 129S6/SvEvTac)F1-derived KV1 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 and subsequently to E2a-Cre mice (Stock No. 003724) to remove the loxP-flanked neo cassette. These mice were backcrossed to C57BL/6J mice (Stock No. 000664) for at least 10 generations by the donating investigator. Upon arrival at The Jackson Laboratory, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes.

Allele

Symbol: Mertk^tm1.1Irb
Name: targeted mutation 1.1, Ira Tabas
MGI accession ID: MGI:6690696
Generation method: Targeted
Attributes: Modified isoform(s)
Synonyms: Mertk^CR; MerTK^delta483-488
Marker symbol: Mertk
Marker name: c-mer proto-oncogene tyrosine kinase
Marker synonyms: c-Eyk; c-mer; Eyk; MER; nmf12; Nyk; rdy; RP38; Tyro 12; Tyro12
Chromosome: 2
Strain of origin: (C57BL/6J x 129S6/SvEvTac)F1
Molecular note: Codons 483-488 were deleted and a downstream Neo cassette (NeoR) flanked by LoxP sites was inserted. The neomycin selection cassette was removed via Cre-mediated recombination in the germline.