APLP2, A MEMBER OF THE ALZHEIMER PRECURSOR PROTEIN FAMILY, IS REQUIRED FOR CORRECT GENOMIC SEGREGATION IN DIVIDING MOUSE CELLS

The mouse amyloid precursor-like protein 2 (APLP2) belongs to the Alzh eimer peptide precursor family. A possible role in pre-implantation de velopment had been suggested previously, and was investigated further by creating a large deletion in the genomic locus. While heterozygous mice developed normally, homozygous embryos were arrested before reach ing the blastocyst stage, One-cell embryos which contained protein of maternal origin underwent a limited number of cleavages. The progressi ve disappearance of the protein at stages 4 and beyond correlated with the appearance of extensive cytopathological effects. Nuclear DNA con tents of the arrested embryos departed widely from the normal 2-4C val ue, thus suggesting a role for the protein in replication and/or segre gation of the embryonic genome. Embryonic mortality was not due to the untimely initiation of programmed cell death, and it occurred before the stage at which apoptotic cells normally appear. The same abnormal distribution of DNA contents was seen in primary cultures of Aplp2 +/- embryonic fibroblasts following transfection of an expression vector for Aplp2 antisense RNA with green fluorescent protein (GFP) expressed from a co-transfected construct, Daughter cells derived from a GFP-po sitive cell showed abnormal DNA contents both >4C and <2C, thus indica ting a role for the protein in the mitotic segregation of the genome a nd establishment of the proper nuclear structure.