B6;129S6-Apbb1^tm1Her/J

Stock number: 012865
Research areas: Cell Biology Research, Developmental Biology Research, Mouse/Human Gene Homologs, Neurobiology Research, Research Tools

Description

The FE65 knockout allele has a nuclear localized-lacZ replacing exon 2 of the Apbb1 gene. These FE65 mutant mice, along with FE65L1 mutant mice, may be useful in studying brain development (neuronal positioning and establishment of axonal projections) and abnormal brain morphology (Cobblestone Lissencephaly, marginal zone heterotopias, and pial basement membrane integrity); as well as the function of FE65 family proteins in amyloid precursor protein (APP) processing, Alzheimer's disease, and neuronal protein trafficking.

Detailed description

The FE65 knockout allele has a nuclear localized-lacZ replacing exon 2 of the Apbb1 gene. No protein expression is detected from the mutant locus, and the donating investigator reports that whether lacZ staining faithfully reflects FE65 expression has not been conclusively resolved. Homozygous (FE65-/-) mice are viable, fertile, and indistinguishable from wildtype littermates. Histological examination of adult brains shows no obvious neuroanatomical abnormalities. These FE65 mutant mice may be useful in studying brain development (neuronal positioning and establishment of axonal projections) and abnormal brain morphology (Cobblestone Lissencephaly, marginal zone heterotopias, and pial basement membrane integrity); as well as the function of FE65 family proteins in amyloid precursor protein (APP) processing, Alzheimer's disease, and neuronal protein trafficking.

For example, mice homozygous for both this FE65 knockout allele and the FE65L1 knockout allele (see Stock No. 012869) exhibit postnatal lethality (partial penetrance), are smaller than their wildtype or heterozygous littermates, and often display bilateral circling. While routine histological staining of the major organs in double knockout (FE65-/-;FE65L1-/-) mice reveals no overt anatomical abnormalities, FE65-/-;FE65L1-/- mice display cortical dysplasia with heterotopias resembling those of Cobblestone Lissencephaly. Specifically, FE65-/-;FE65L1-/- mice exhibit neuroanatomical abnormalities in the cortex and hippocampus that include marginal zone heterotopias (migration of heterotopic neurons beyond the marginal zone and located in the wrong part of the brain), midline crossing defects, and axonal pathfinding abnormalities. The phenotype of FE65-/-;FE65L1-/- mice shares remarkable similarities with that reported for mutant mice lacking FE65-binding partners, the three members of the APP gene family (APP, APLP1 and APLP2), and the Ena/Vasp protein family.

Development

These FE65 mutant mice were created in the laboratory of Dr. Joachim Herz (University of Texas Southwestern Medical Center, Dallas). A targeting vector was designed to replace 6.5 kb of the FE65 (Apbb1) locus (including the C-terminal 77 nucleotides of exon 2, intron 2 and the N-terminal 158 nucleotides of exon 3) with a β-galactosidase (lacZ) with nuclear localization signal and oppositely-oriented pol2neo cassette. This construct was electroporated into 129S6/SvEvTac-derived SM1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts and chimeric males were bred with C57BL/6J inbred females to establish the colony. Mutant mice were then bred together for several generations and made homozygous. Therefore, homozygous mice on a mixed C57BL/6J;129SvEvTac genetic background (not C57BL/6;129SvEvBradley as originally reported) were sent to The Jackson Laboratory Repository. Upon arrival, mice were bred to C57BL/6J (Stock No. 000664) for at least one generation to establish the colony.

Allele

Symbol: Apbb1^tm1Her
Name: targeted mutation 1, Joachim Herz
MGI accession ID: MGI:3615373
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: Apbb1^tm1Sgnt; Fe65^-; p97/60FE65^-
Marker symbol: Apbb1
Marker name: amyloid beta (A4) precursor protein-binding, family B, member 1
Marker synonyms: FE65; MGC:9072; Rir
Chromosome: 7
Strain of origin: 129S6/SvEvTac
Molecular note: A targeting vector was designed to replace 6.5 kb of sequence with a pol2neo cassette and a lacZ into exon 2. Deleted sequence contained the C-terminal 77 nucleotides of exon 2, intron 2 and the N-terminal 158 nucleotides of exon 3. Protein was not detected by Western blot analysis.