Impairment of radial glial scaffold-dependent neuronal migration and formation of double cortex by genetic ablation of afadin.

Abstract

Studies of human brain malformations, such as lissencephaly and double cortex, have revealed the importance of neuronal migration during cortical development. Afadin, a membrane scaffolding protein, regulates the formation of adherens junctions (AJs) and cell migration to form and maintain tissue structures. Here, we report that mice with dorsal telencephalon-specific ablation of afadin gene exhibited defects similar to human double cortex, in which the heterotopic cortex was located underneath the normotopic cortex. The normotopic cortex of the mutant mice was arranged in the pattern similar to the cortex of the control mice, while the heterotopic cortex was disorganized. As seen in human patients, double cortex in the mutant mice was formed by impaired neuronal migration during cortical development. Genetic ablation of afadin in the embryonic cerebral cortex disrupted AJs of radial glial cells, likely resulting in the retraction of the apical endfeet from the ventricular surface and the dispersion of radial glial cells from the ventricular zone to the subventricular and intermediate zones. These results indicate that afadin is required for the maintenance of AJs of radial glial cells and that the disruption of AJs might cause an abnormal radial scaffold for neuronal migration. In contrast, the proliferation or differentiation of radial glial cells was not significantly affected. Taken together, these findings indicate that afadin is required for the maintenance of the radial glial scaffold for neuronal migration and that the genetic ablation of afadin leads to the formation of double cortex.

• Authors: Hideaki Yamamoto, Kenji Mandai, Daijiro Konno, Tomohiko Maruo, Fumio Matsuzaki, Yoshimi Takai
• Journal: Brain research (Brain Res) Vol. 1620 Pg. 139-52 (Sep 16 2015) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 25988834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Afdn protein, mouse
• Myosins
• Kinesins

Topics

• Animals
• Animals, Newborn
• Cell Movement (physiology)
• Cerebral Cortex (embryology, pathology, physiopathology)
• Classical Lissencephalies and Subcortical Band Heterotopias (pathology, physiopathology)
• Disease Models, Animal
• Fluorescent Antibody Technique
• Kinesins (deficiency, genetics)
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Confocal
• Myosins (deficiency, genetics)
• Neuroglia (pathology, physiology)
• Neurons (pathology, physiology)