Presenilin 1 Is Required for Notch1 and DII1 Expression in the Paraxial Mesoderm

Nature. 1997 May 15;387(6630):288-92. doi: 10.1038/387288a0.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Body Patterning / genetics
  • Body Patterning / physiology
  • Central Nervous System / blood supply
  • Central Nervous System / embryology
  • Embryonic and Fetal Development / genetics
  • Embryonic and Fetal Development / physiology
  • Gene Targeting
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Mesoderm / metabolism*
  • Mice
  • Presenilin-1
  • Protein Precursors / physiology
  • Receptor, Notch1
  • Receptors, Cell Surface*
  • Transcription Factors*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Notch1 protein, mouse
  • Presenilin-1
  • Protein Precursors
  • Receptor, Notch1
  • Receptors, Cell Surface
  • Transcription Factors
  • delta protein