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  • The EMBO Journal (2004) 23, 4106 - 4115
  • doi:10.1038/sj.emboj.7600390

Published online: 23 September 2004

Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members

Jochen Herms1, Brigitte Anliker2,a, Sabine Heber2, Sabine Ring2, Martin Fuhrmann1, Hans Kretzschmar1, Sangram Sisodia3 and Ulrike Müller2

  1. Zentrum für Neuropathologie und Prionforschung, Universität München, München, Germany
  2. Department of Neurochemistry, Max-Planck-Institute for Brain Research, Frankfurt, Germany
  3. Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, IL, USA

Correspondence to:

Ulrike Müller, Department of Neurochemistry, Max-Planck-Institute for Brain Research, Deutschordenstr. 46, 60528 Frankfurt, Germany. Tel.: +49 69 96769 317; Fax: +49 69 96769 441; E-mail: umueller@mpih-frankfurt.mpg.de

aPresent address: Department of Molecular Biology ICND-118, The Scripps Research Institute, La Jolla, CA 92037, USA

Received 18 February 2004; Accepted 9 August 2004

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.

  • Keywords:

    • Alzheimer's disease,
    • APLP,
    • beta-amyloid precursor protein,
    • lissencephaly,
    • triple knockout
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