B6.129-Sh3glb1^tm1Hgw/J

Stock number: 025850
Product name: bif-1 KO
Research areas: Cancer Research, Internal/Organ Research, Research Tools

Description

This bif-1 (Sh3glb1) knock-out strain is useful in studies of activation of apoptosis, autophagy, mitophagy and tumorigenesis.

Detailed description

The mitochondrial endophilin B1 protein, also known as endophilin B1 and SH3GLB1, encoded by the Sh3glb1 gene, interacts with BAX (BCL2-associated X protein) to regulate apoptosis and with BECN1 (beclin 1, autophagy related) to regulate autophagy and tumorigenesis. These bif-1 knock-out mice carry a mutant allele in which exon 1 and the translation initiation site have been replaced by a NEO cassette. Mutant null mice (6-18 months of age) on a mixed genetic background of 129SV/J and C57BL/6 exhibit enlarged spleens compared to wildtype controls. By 12 months of age, most homozygotes (almost 90%) develop spontaneous tumors. Lymphoma, hepatocellular carcinoma, sarcoma, esophageal squamous cell carcinoma, small cell lung carcinoma, and duodenal adenocarcinoma have been identified. . Moreover, homozygous mice on a C57BL/6 background develop obesity under both regular chow and high-fat diets and display a moderate impairment of insulin signaling. Fragmented depolarized mitochondria are observed in neurons from homozygotes. As a result of ischemic stroke (induced by middle cerebral artery occlusion), homozygotes exhibit larger infarcts and enhanced astrogliosis compared to wildtype controls. Cultured primary postnatal cortical neurons from homozygotes exhibit increased sensitivity to neurotoxic treatment, fewer mitochondria in neurites, and smaller, shorter mitochondria. In a model of autophagy-dependent clearance of damaged mitochondria, homozygotes respond with an accumulation of immature autophagosomes. Mice that are homozygous for the KO allele are viable and fertile. No gene product (protein) is detected by immunoblot analysis of homozygotes.





When crossed to a mouse model of B-cell lymphoma (see Stock No. 002728, for example), the double mutant mice (carrying the transgene and homozygous for the Sh3glb1^tm1Hgw allele) exhibit accelerated tumor onset and mortality, chromosomal instability, and increased mitochondrial mass.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development

A targeting vector designed by Dr. Hong-Gang Wang (University of South Florida College of Medicine) containing a NEO cassette was used to disrupt exon 1 and the translation initiation start site. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-Kitl⁺ derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to C57BL/6 mice, and then backcrossed to C57BL/6 for more than 20 generations. Heterozygous sperm was cryopreserved. Upon arrival, to establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).

Allele

Symbol: Sh3glb1^tm1Hgw
Name: targeted mutation 1, Hong-Gang Wang
MGI accession ID: MGI:3608890
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: bif-1^-
Marker symbol: Sh3glb1
Marker name: SH3-domain GRB2-like B1 (endophilin)
Marker synonyms: Bif-1; CGI-61; dJ612B15.2; Endophilin B1; PPP1R70
Chromosome: 3
Strain of origin: (129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Molecular note: A targeting construct was designed to replace exon 1 and the translation start site. Immunoblots of whole cell lysates confirmed absence of protein in mutant embryos.