Journal
EMBO JOURNAL
Volume 23, Issue 20, Pages 4106-4115Publisher
WILEY
DOI: 10.1038/sj.emboj.7600390
Keywords
Alzheimer's disease; APLP; beta-amyloid precursor protein; lissencephaly; triple knockout
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The Alzheimer's disease beta-amyloid precursor protein (APP) is a member of a larger gene family that includes the amyloid precursor-like proteins, termed APLP1 and APLP2. We previously documented that APLP2(-/-) APLP1(-/-) and APLP2(-/-) APP(-/-) mice die postnatally, while APLP1(-/-) APP(-/-) mice and single mutants were viable. We now report that mice lacking all three APP/ APLP family members survive through embryonic development, and die shortly after birth. In contrast to double-mutant animals with perinatal lethality, 81% of triple mutants showed cranial abnormalities. In 68% of triple mutants, we observed cortical dysplasias characterized by focal ectopic neuroblasts that had migrated through the basal lamina and pial membrane, a phenotype that resembles human type II lissencephaly. Moreover, at E18.5 triple mutants showed a partial loss of cortical Cajal Retzius (CR) cells, suggesting that APP/APLPs play a crucial role in the survival of CR cells and neuronal adhesion. Collectively, our data reveal an essential role for APP family members in normal brain development and early postnatal survival.
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