title: Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members.
abstract: 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.
authors.affiliation: Zentrum für Neuropathologie und Prionforschung, Universität München, München, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
authors.forename: Brigitte
authors.initials: B
authors.lastname: Anliker
authors.forename: Sabine
authors.initials: S
authors.lastname: Heber
authors.forename: Sabine
authors.initials: S
authors.lastname: Ring
authors.forename: Martin
authors.initials: M
authors.lastname: Fuhrmann
authors.forename: Hans
authors.initials: H
authors.lastname: Kretzschmar
authors.forename: Sangram
authors.initials: S
authors.lastname: Sisodia
authors.forename: Ulrike
authors.initials: U
authors.lastname: Müller
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000145:classification / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000473:pathology*; D003433:Crosses, Genetic; D047108:Embryonic Development; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D012886:Skull / Q000002:abnormalities; D015996:Survival Rate
chemical_list: D016564:Amyloid beta-Protein Precursor