title: Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm.
abstract: Approximately 10% of cases of Alzheimer's disease are familial and associated with autosomal dominant inheritance of mutations in genes encoding the amyloid precursor protein, presenilin 1 (PS1) and presenilin 2 (PS2). Mutations in PS1 are linked to about 25% of cases of early-onset familial Alzheimer's disease. PS1, which is endoproteolytically processed in vivo, is a multipass transmembrane protein and is a functional homologue of SEL-12, a Caenorhabditis elegans protein that facilitates signalling mediated by the Notch/LIN-12 family of receptors. To examine potential roles for PS1 in facilitating Notch-mediated signalling during mammalian embryogenesis, we generated mice with targeted disruptions of PS1 alleles (PS1-/- mice). PS1-/- embryos exhibited abnormal patterning of the axial skeleton and spinal ganglia, phenotypes traced to defects in somite segmentation and differentiation. Moreover, expression of mRNA encoding Notch1 and Dll1 (delta-like gene 1), a vertebrate Notch ligand, is markedly reduced in the presomitic mesoderm of PS1-/- embryos compared to controls. Hence, PS1 is required for the spatiotemporal expression of Notch1 and Dll1, which are essential for somite segmentation and maintenance of somite borders.
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. pcwong@welchlink.welch.jhu.edu
authors.forename: P C
authors.initials: PC
authors.lastname: Wong
authors.forename: H
authors.initials: H
authors.lastname: Zheng
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: M W
authors.initials: MW
authors.lastname: Becher
authors.forename: D J
authors.initials: DJ
authors.lastname: Sirinathsinghji
authors.forename: M E
authors.initials: ME
authors.lastname: Trumbauer
authors.forename: H Y
authors.initials: HY
authors.lastname: Chen
authors.forename: D L
authors.initials: DL
authors.lastname: Price
authors.forename: L H
authors.initials: LH
authors.lastname: Van der Ploeg
authors.forename: S S
authors.initials: SS
authors.lastname: Sisodia
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics / Q000502:physiology; D002490:Central Nervous System / Q000098:blood supply / Q000196:embryology; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology; D018390:Gene Targeting; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D053764:Presenilin-1; D011498:Protein Precursors / Q000502:physiology; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D053764:Presenilin-1; D011498:Protein Precursors; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C064045:delta protein