FVB.129S2(B6)-Nr4a1^tm1Jmi/HzengJ

Stock number: 028205
Product name: Nur77-/-(Fvb)
Research areas: Diabetes and Obesity Research, Internal/Organ Research, Metabolism Research, Neurobiology Research, Research Tools

Description

These NGFI-B or Nur77 mutant mice are on a congenic FVB/N background and may be useful in studies related to tumor growth, wound healing, angiogenesis and inflammation. Although the original analysis of this allele revealed no detectable transcript of any type from this gene in the thymus, findings by Koenis, 2018 (PMID 30111591) indicate the presence of a transcript capable of producing a truncated N-terminal domain (NTD) peptide that can stabilize and activate HIF1A  (hypoxia inducible factor 1, alpha subunit).

Detailed description

The orphan nuclear transcription factor encoded by the Nr4a1 gene is involved in neuron development & maintenance, myofiber size and muscle mass, wound healing, progesterone receptor-mediated permeability responses in uterine embryo implantation, angiogenesis, anti-inflammation, and glucose homeostasis. These NGFI-B or Nur77 mutant mice carry a targeted mutation in which a PGK-NEO cassette disrupts exon 2. Mice homozygous for the allele and on a congenic FVB/N background are viable and fertile. The Donating Investigator reports that the congenic FVB/N background does not alter the phenotype observed in B6;129 mixed and congenic C57BL/6 Nr4a1^tm1Jmi mutant mice. On the C57BL/6 background, knock-out mice have greatly diminished angiogenic response to VEGF-A, histamine or serotonin induction, and are more susceptible to diet-induced obesity and insulin resistance.

Of note, although the original analysis of this allele revealed no detectable transcript of any type from this gene in the thymus, findings by Koenis, 2018 (PMID 30111591) indicate the presence of a transcript capable of producing a truncated N-terminal domain (NTD) peptide that can stabilize and activate HIF1A  (hypoxia inducible factor 1, alpha subunit). Neither the transcriptional nor the translational start of the gene are disrupted.

Development

A targeting vector was designed by Jeffrey Milbrandt (Washington University in St. Louis), to insert a phosphoglycerate kinase-neomycin resistance cassette (PGK-neo) cassette into the coding region of exon 2 of the Nr4a1 gene. This construct was electroporated into 129S2/SvPas-derived D3 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. Chimeric males were bred with C57BL/6J females to establish heterozygous mice. The mice were backcrossed to C57BL/6 for several generations. Dr. Huiyan Zeng obtained mice from Dr. Milbrandt and backcrossed the mice to FVB/N for 10 generations. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize FVB/NJ oocytes (Stock No. 001800).

Allele

Symbol: Nr4a1^tm1Jmi
Name: targeted mutation 1, Jeffrey Milbrandt
MGI accession ID: MGI:2182325
Generation method: Targeted
Attributes: Not Specified
Marker symbol: Nr4a1
Marker name: nuclear receptor subfamily 4, group A, member 1
Chromosome: 15
Strain of origin: 129S2/SvPas
Molecular note: Exon 2 was disrupted by the insertion of a neomycin resistance gene 300 bp downstream of the translational start site. A functional portion of the N-terminal domain of the full length gene is expressed.