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The Journal of Neuroscience, July 1, 2009, 29(26):8578-8585; doi:10.1523/JNEUROSCI.0958-09.2009

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Development/Plasticity/Repair
Reelin and Notch1 Cooperate in the Development of the Dentate Gyrus

Mirjam Sibbe,¹ Eckart Förster,² Onur Basak,³ Verdon Taylor,³ and Michael Frotscher¹

¹Institute of Anatomy and Cell Biology, University of Freiburg, D-79104 Freiburg, Germany, ²Institute of Anatomy I: Cellular Neurobiology, University Medical Center, D-20246 Hamburg, Germany, and ³Department of Molecular Embryology, Max Planck Institute of Immunobiology, D-79108 Freiburg, Germany

Correspondence should be addressed to Mirjam Sibbe, Institute of Anatomy and Cell Biology, University of Freiburg, Albertstrasse 17, D-79104 Freiburg, Germany. Email: Mirjam.Sibbe{at}anat.uni-freiburg.de

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.

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Received Feb. 26, 2009; revised March 23, 2009; accepted March 23, 2009.

Correspondence should be addressed to Mirjam Sibbe, Institute of Anatomy and Cell Biology, University of Freiburg, Albertstrasse 17, D-79104 Freiburg, Germany. Email: Mirjam.Sibbe{at}anat.uni-freiburg.de

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