STOCK Axl^tm1Grl/J

Stock number: 011121
Research areas: Apoptosis Research, Cell Biology Research, Immunology, Inflammation and Autoimmunity Research, Reproductive Biology Research, Research Tools, Virology Research

Description

Mice homozygous for the Axl knockout allele exhibit an overtly normal phenotype - however, in combination with mutations in other receptor tyrosine kinases, this strain may be useful in studies of innate immunity, autoimmunity, germ cell development and apoptosis. Axl is highly expressed by key cellular targets of ZIKA virus (ZIKV), and is proposed to promote viral entry in certain cell types (including non-Axl-expressing cells). Axl inhibition represents a potential approach for antiviral therapies.

Detailed description

Mice that are homozygous for the targeted null mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. When combined with the mutations Tyro3^tm1Grl (Stock No. 007937) and Mertk^tm1Grl (Stock No. 011122), mice exhibit a lymphoproliferative disorder, autoimmunity, increased apoptosis in multiple tissues, blindness, abnormal spermatogenesis and reduced fertility (in females) or infertility (in males).

The TAM receptors (Tyro3, Axl, and Mertk) are a family of receptor tyrosine kinases whose ligands (Gas6 and Protein S) bind to phosphatidylserine on the surface of apoptotic cells and enveloped viruses. Axl is highly expressed by key cellular targets of ZIKA virus (ZIKV) - including human radial glial cells, astrocytes, endothelial cells and microglia in developing human cortex, and by progenitor cells in developing retina (Nowakowski et al. 2016 Cell Stem Cell 18:591), as well as in subtypes of trophoblasts (Tabata et al. 2016 Cell Host Microb. 20:155). Research in 2017 identifies a dual role of Axl during ZIKV infection of human glial cells (astrocytes and microglia) - promoting viral entry and modulating innate immune responses - and suggests Axl inhibition may represent a potential target for antiviral therapies (Meertens et al. 2017 Cell Rep. 18:324).

Development

A targeting vector was designed to introduce a neomycin resistance cassette into exon 9. The construct was electroporated into CB1-4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were intercrossed to generate homozygotes. Upon arrival at The Jackson Laboratory, mutant mice were bred to B6129SF2/J inbred mice (Stock No. 101045) to establish the colony.

Allele

Symbol: Axl^tm1Grl
Name: targeted mutation 1, Greg Lemke
MGI accession ID: MGI:2387750
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Axl
Marker name: AXL receptor tyrosine kinase
Chromosome: 7
Strain of origin: C57BL/6J x (Rb(11.16)2H x Rb(16.17)32Lub)F1
Molecular note: A neomycin selection cassette replaced a segment of the gene containing exon 9. Western blot analysis on total brain lysates derived from homozygous mice demonstrated that no detectable protein was produced from this allele.