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J Neurosci. 2018 Jan 3;38(1):137-148. doi: 10.1523/JNEUROSCI.0988-17.2017. Epub 2017 Nov 14.

Trajectory Analysis Unveils Reelin's Role in the Directed Migration of Granule Cells in the Dentate Gyrus.

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Institute for Structural Neurobiology, Center for Molecular Neurobiology (ZMNH), 20251 Hamburg, Germany.
Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
College of Veterinary Medicine, Northwest A&F University, 712100 Yangling, China.
College of Basic Medicine, Gansu University of Chinese Medicine, 730000 Lanzhou, China.
UKE Microscopy Imaging Facility, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Institute of Anatomy and Cell Biology, University of Freiburg, 79104 Freiburg, Germany.
Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, and.
Institute for Structural Neurobiology, Center for Molecular Neurobiology (ZMNH), 20251 Hamburg, Germany,


Reelin controls neuronal migration and layer formation. Previous studies in reeler mice deficient in Reelin focused on the result of the developmental process in fixed tissue sections. It has remained unclear whether Reelin affects the migratory process, migration directionality, or migrating neurons guided by the radial glial scaffold. Moreover, Reelin has been regarded as an attractive signal because newly generated neurons migrate toward the Reelin-containing marginal zone. Conversely, Reelin might be a stop signal because migrating neurons in reeler, but not in wild-type mice, invade the marginal zone. Here, we monitored the migration of newly generated proopiomelanocortin-EGFP-expressing dentate granule cells in slice cultures from reeler, reeler-like mutants and wild-type mice of either sex using real-time microscopy. We discovered that not the actual migratory process and migratory speed, but migration directionality of the granule cells is controlled by Reelin. While wild-type granule cells migrated toward the marginal zone of the dentate gyrus, neurons in cultures from reeler and reeler-like mutants migrated randomly in all directions as revealed by vector analyses of migratory trajectories. Moreover, live imaging of granule cells in reeler slices cocultured to wild-type dentate gyrus showed that the reeler neurons changed their directions and migrated toward the Reelin-containing marginal zone of the wild-type culture, thus forming a compact granule cell layer. In contrast, directed migration was not observed when Reelin was ubiquitously present in the medium of reeler slices. These results indicate that topographically administered Reelin controls the formation of a granule cell layer.SIGNIFICANCE STATEMENT Neuronal migration and the various factors controlling its onset, speed, directionality, and arrest are poorly understood. Slice cultures offer a unique model to study the migration of individual neurons in an almost natural environment. In the present study, we took advantage of the expression of proopiomelanocortin-EGFP by newly generated, migrating granule cells to analyze their migratory trajectories in hippocampal slice cultures from wild-type mice and mutants deficient in Reelin signaling. We show that the compartmentalized presence of Reelin is essential for the directionality, but not the actual migratory process or speed, of migrating granule cells leading to their characteristic lamination in the dentate gyrus.


Dab1 phosphorylation; Reelin; hippocampus; live imaging; neuronal migration; reeler-like

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