Interaction of reelin signaling and Lis1 in brain development

Nat Genet. 2003 Nov;35(3):270-6. doi: 10.1038/ng1257. Epub 2003 Oct 26.

Abstract

Loss-of-function mutations in RELN (encoding reelin) or PAFAH1B1 (encoding LIS1) cause lissencephaly, a human neuronal migration disorder. In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers. Pafah1b1(+/-) mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal. Reln encodes an extracellular protein that regulates layer formation by interacting with VLDLR and ApoER2 (Lrp8) receptors, thereby phosphorylating the Dab1 signaling molecule. Lis1 associates with microtubules and modulates neuronal migration. We investigated interactions between the reelin signaling pathway and Lis1 in brain development. Compound mutant mice with disruptions in the Reln pathway and heterozygous Pafah1b1 mutations had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. Dab1 and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicate genetic and biochemical interaction between the reelin signaling pathway and Lis1.

Publication types

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

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Animals
  • Brain / embryology*
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Extracellular Matrix Proteins / metabolism*
  • Humans
  • Mice
  • Mice, Neurologic Mutants
  • Microtubule-Associated Proteins / metabolism*
  • Nerve Tissue Proteins
  • Serine Endopeptidases
  • Signal Transduction*

Substances

  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • PAFAH1B1 protein, human
  • Pafah1b1 protein, mouse
  • Serine Endopeptidases
  • reelin protein