1. The Secreted Glycoprotein Reelin Suppresses the Proliferation and Regulates the Distribution of Oligodendrocyte Progenitor Cells in the Embryonic Neocortex
- Author
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Kazunori Nakajima, Kohki Toriuchi, Tsuzumi Nakajima, Mitsuharu Hattori, Mineyoshi Aoyama, Himari Ogino, and Yuki Hirota
- Subjects
Male ,0301 basic medicine ,Cell signaling ,Cell Adhesion Molecules, Neuronal ,Neurogenesis ,Neocortex ,Nerve Tissue Proteins ,Mice ,03 medical and health sciences ,ADAMTS Proteins ,0302 clinical medicine ,Neural Stem Cells ,medicine ,Animals ,Reelin ,Progenitor cell ,Cells, Cultured ,Research Articles ,Extracellular Matrix Proteins ,biology ,General Neuroscience ,Serine Endopeptidases ,DAB1 ,Embryonic stem cell ,Oligodendrocyte ,Cell biology ,Mice, Inbred C57BL ,Oligodendroglia ,Reelin Protein ,stomatognathic diseases ,030104 developmental biology ,medicine.anatomical_structure ,Receptors, LDL ,nervous system ,biology.protein ,Female ,Signal transduction ,030217 neurology & neurosurgery ,Protein Binding - Abstract
Oligodendrocyte (OL) progenitor cells (OPCs) are generated, proliferate, migrate, and differentiate in the developing brain. Although the development of OPCs is prerequisite for normal brain function, the molecular mechanisms regulating their development in the neocortex are not fully understood. Several molecules regulate the tangential distribution of OPCs in the developing neocortex, but the cue molecule(s) that regulate their radial distribution remains unknown. Here, we demonstrate that the secreted glycoprotein Reelin suppresses the proliferation of OPCs and acts as a repellent for their migrationin vitro. These functions rely on the binding of Reelin to its receptors and on the signal transduction involving the intracellular protein Dab1. In the late embryonic neocortex of mice with attenuated Reelin signaling [i.e., Reelin heterozygote-deficient, Dab1 heterozygote-deficient mutant, or very low-density lipoprotein receptor (VLDLR)-deficient mice], the number of OPCs increased and their distribution shifted toward the superficial layers. In contrast, the number of OPCs decreased and they tended to distribute in the deep layers in the neocortex of mice with abrogated inactivation of Reelin by proteolytic cleavage, namely a disintegrin and metalloproteinase with thrombospondin type 1 motifs 3 (ADAMTS-3)-deficient mice and cleavage-resistant Reelin knock-in mice. Both male and female animals were used. These data indicate that Reelin–Dab1 signaling regulates the proliferation and radial distribution of OPCs in the late embryonic neocortex and that the regulation of Reelin function by its specific proteolysis is required for the normal development of OPCs.SIGNIFICANCE STATEMENTHere, we report that Reelin–Dab1 signaling regulates the proliferation and radial distribution of OPCs in the late embryonic mouse neocortex. Oligodendrocyte (OL) progenitor cells (OPCs) express Reelin signaling molecules and respond to Reelin stimulation. Reelin–Dab1 signaling suppresses the proliferation of OPCs bothin vitroandin vivo. Reelin repels OPCsin vitro, and the radial distribution of OPCs is altered in mice with either attenuated or augmented Reelin–Dab1 signaling. This is the first report identifying the secreted molecule that plays a role in the radial distribution of OPCs in the late embryonic neocortex. Our results also show that the regulation of Reelin function by its specific proteolysis is important for the normal development of OPCs.
- Published
- 2020
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