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.