Reelin and Notch1 cooperate in the development of the dentate gyrus.
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.
Sibbe
Mirjam
M
Institute of Anatomy and Cell Biology, University of Freiburg, D-79104 Freiburg, Germany. Mirjam.Sibbe@anat.uni-freiburg.de
Förster
Eckart
E
Basak
Onur
O
Taylor
Verdon
V
Frotscher
Michael
M
D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000502:physiology*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects; D046509:Tissue Culture Techniques; D014162:Transfection / Q000379:methods
D015816:Cell Adhesion Molecules, Neuronal; C103773:Dab1 protein, mouse; D004151:Dipeptides; D016326:Extracellular Matrix Proteins; C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D009419:Nerve Tissue Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D000091042:Reelin Protein; D049452:Green Fluorescent Proteins; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D010751:Phosphopyruvate Hydratase