期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：37
DOI：10.1073/pnas.2120079119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
The present study highlights a fundamental role of GABAergic interneuron-derived Reelin in neuronal migration, in addition to CR cell–expressed Reelin. Further, we observed transient migratory deficits, indicating that Reelin expressed by either neuronal population is sufficient to reverse some lamination defects. We propose a model of Reelin action in corticogenesis based on the spatial and cell-specific expression of this key protein. Because several neuropsychiatric disorders are linked to Reelin deficits in interneurons, this study may provide a better understanding of the mechanisms associated with human brain disorders related to Reelin deficits.
The extracellular protein Reelin, expressed by Cajal–Retzius (CR) cells at early stages of cortical development and at late stages by GABAergic interneurons, regulates radial migration and the “inside-out” pattern of positioning. Current models of Reelin functions in corticogenesis focus on early CR cell–derived Reelin in layer I. However, developmental disorders linked to Reelin deficits, such as schizophrenia and autism, are related to GABAergic interneuron–derived Reelin, although its role in migration has not been established. Here we selectively inactivated the
Reln gene in CR cells or GABAergic interneurons. We show that CR cells have a major role in the inside-out order of migration, while CR and GABAergic cells sequentially cooperate to prevent invasion of cortical neurons into layer I. Furthermore, GABAergic cell–derived Reelin compensates some features of the
reeler phenotype and is needed for the fine tuning of the layer-specific distribution of cortical neurons. In the hippocampus, the inactivation of Reelin in CR cells causes dramatic alterations in the dentate gyrus and mild defects in the hippocampus proper. These findings lead to a model in which both CR and GABAergic cell–derived Reelin cooperate to build the inside-out order of corticogenesis, which might provide a better understanding of the mechanisms involved in the pathogenesis of neuropsychiatric disorders linked to abnormal migration and Reelin deficits.
