Reelin and Notch1 cooperate in the development of the dentate gyrus

J Neurosci. 2009 Jul 1;29(26):8578-85. doi: 10.1523/JNEUROSCI.0958-09.2009.

Abstract

The development of the hippocampal dentate gyrus is a complex process in which several signaling pathways are involved and likely interact with each other. The extracellular matrix molecule Reelin is necessary both for normal development of the dentate gyrus radial glia and neuronal migration. In Reelin-deficient Reeler mice, the hippocampal radial glial scaffold fails to form, and granule cells are dispersed throughout the dentate gyrus. Here, we show that both formation of the radial glia scaffold and lamination of the dentate gyrus depend on intact Notch signaling. Inhibition of Notch signaling in organotypic hippocampal slice cultures induced a phenotype reminiscent of the Reelin-deficient hippocampus, i.e., a reduced density of radial glia fibers and granule cell dispersion. Moreover, a Reelin-dependent rescue of the Reeler phenotype was blocked by inhibition of Notch activation. In the Reeler dentate gyrus, we found reduced Notch1 signaling; the activated Notch intracellular domain as well as the transcriptional targets, brain lipid-binding protein, and Hes5 are decreased. Disabled1, a component of the Reelin-signaling pathway colocalizes with Notch1, thus indicating a direct interaction between the Reelin- and Notch1-signaling pathways. These results suggest that Reelin enhances Notch1 signaling, thereby contributing to the formation of the radial glial scaffold and the normal development of the dentate gyrus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Genetically Modified
  • Animals, Newborn
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / pharmacology
  • Cell Adhesion Molecules, Neuronal / physiology*
  • Cell Count / methods
  • Cells, Cultured
  • Dentate Gyrus / cytology
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / growth & development*
  • Dentate Gyrus / metabolism
  • Dipeptides / pharmacology
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / pharmacology
  • Extracellular Matrix Proteins / physiology*
  • Fatty Acid-Binding Protein 7
  • Fatty Acid-Binding Proteins / metabolism
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology*
  • Glial Fibrillary Acidic Protein / metabolism
  • Green Fluorescent Proteins / genetics
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / pharmacology
  • Nerve Tissue Proteins / physiology
  • Phosphopyruvate Hydratase / metabolism
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / physiology*
  • Reelin Protein
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / pharmacology
  • Serine Endopeptidases / physiology*
  • Stem Cells / drug effects
  • Tissue Culture Techniques
  • Transfection / methods

Substances

  • Cell Adhesion Molecules, Neuronal
  • Dab1 protein, mouse
  • Dipeptides
  • Extracellular Matrix Proteins
  • Fabp7 protein, mouse
  • Fatty Acid-Binding Protein 7
  • Fatty Acid-Binding Proteins
  • Glial Fibrillary Acidic Protein
  • N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
  • Nerve Tissue Proteins
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Reelin Protein
  • Green Fluorescent Proteins
  • RELN protein, human
  • Reln protein, mouse
  • Serine Endopeptidases
  • Phosphopyruvate Hydratase