title: Embryonic mosaic deletion of APP results in displaced Reelin-expressing cells in the cerebral cortex.
abstract: It is widely accepted that amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer's disease. In addition, APP has been proposed to have functions in numerous biological processes including neuronal proliferation, differentiation, migration, axon guidance, and neurite outgrowth, as well as in synapse formation and function. However, germline knockout of APP yields relatively subtle phenotypes, and brain development appears grossly normal. This is thought to be due in part to functional compensation by APP family members and other type I transmembrane proteins. Here, we have generated a conditional mouse knockout for APP that is controlled temporally using CreERand tamoxifen administration. We show that total cortical expression of APP is reduced following tamoxifen administration during embryonic time points critical for cortical lamination, and that this results in displacement of Reelin-positive cells below the cortical plate with a concurrent elevation in Reelin protein levels. These results support a role for APP in cortical lamination and demonstrate the utility of a conditional knockout approach in which APP can be deleted with temporal control in vivo. This new tool should be useful for many different applications in the study of APP function across the mammalian life span.
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Callahan
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Taylor
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tilearcio
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: T
authors.initials: T
authors.lastname: Cavanaugh
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Selkoe
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: tyoung@rics.bwh.harvard.edu.
authors.forename: T L
authors.initials: TL
authors.lastname: Young-Pearse
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D005854:Germ Cells / Q000378:metabolism; D018345:Mice, Knockout; D009030:Mosaicism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases
keywords: APP; Alzheimer's; Cortex; Development; Migration; Reelin