Premium
Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members
Author(s) -
Herms Jochen,
Anliker Brigitte,
Heber Sabine,
Ring Sabine,
Fuhrmann Martin,
Kretzschmar Hans,
Sisodia Sangram,
Müller Ulrike
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600390
Subject(s) - lissencephaly , biology , cortical dysplasia , type (biology) , genetics , gene , neuroscience , epilepsy , ecology
The Alzheimer's disease β‐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.