title: Importance of Reelin C-terminal region in the development and maintenance of the postnatal cerebral cortex and its regulation by specific proteolysis.
abstract: During brain development, Reelin exerts a variety of effects in a context-dependent manner, whereas its underlying molecular mechanisms remain poorly understood. We previously showed that the C-terminal region (CTR) of Reelin is required for efficient induction of phosphorylation of Dab1, an essential adaptor protein for canonical Reelin signaling. However, the physiological significance of the Reelin CTR in vivo remains unexplored. To dissect out Reelin functions, we made a knock-in (KI) mouse in which the Reelin CTR is deleted. The amount of Dab1, an indication of canonical Reelin signaling strength, is increased in the KI mouse, indicating that the CTR is necessary for efficient induction of Dab1 phosphorylation in vivo. Formation of layer structures during embryonic development is normal in the KI mouse. Intriguingly, the marginal zone (MZ) of the cerebral cortex becomes narrower at postnatal stages because upper-layer neurons invade the MZ and their apical dendrites are misoriented and poorly branched. Furthermore, Reelin undergoes proteolytic cleavage by proprotein convertases at a site located 6 residues from the C terminus, and it was suggested that this cleavage abrogates the Reelin binding to the neuronal cell membrane. Results from ectopic expression of mutant Reelin proteins in utero suggest that the dendrite development and maintenance of the MZ require Reelin protein with an intact CTR. These results provide a novel model regarding Reelin functions involving its CTR, which is not required for neuronal migration during embryonic stages but is required for the development and maintenance of the MZ in the postnatal cerebral cortex.
authors: Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Aichi 467-8603, Japan, and.
authors: Takao
authors: T
authors: Kohno
authors: Department of Anatomy, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors: Takao
authors: T
authors: Honda
authors: Department of Anatomy, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors: Ken-Ichiro
authors: K
authors: Kubo
authors: Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Aichi 467-8603, Japan, and.
authors: Yoshimi
authors: Y
authors: Nakano
authors: Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Aichi 467-8603, Japan, and.
authors: Ayaka
authors: A
authors: Tsuchiya
authors: Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Aichi 467-8603, Japan, and.
authors: Tatsuro
authors: T
authors: Murakami
authors: Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Aichi 467-8603, Japan, and.
authors: Hideyuki
authors: H
authors: Banno
authors: Department of Anatomy, Keio University School of Medicine, Tokyo 160-8582, Japan kazunori@keio.jp mhattori@phar.nagoya-cu.ac.jp.
authors: Kazunori
authors: K
authors: Nakajima
authors: Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Aichi 467-8603, Japan, and kazunori@keio.jp mhattori@phar.nagoya-cu.ac.jp.
authors: Mitsuharu
authors: M
authors: Hattori
mesh_terms: D000818:Animals; D019556:COS Cells; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics* / Q000378:metabolism*; D002540:Cerebral Cortex / Q000254:growth & development* / Q000378:metabolism*; D002522:Chlorocebus aethiops; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism*; D055879:Gene Knock-In Techniques / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D059748:Proteolysis; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases
keywords: Dab1; Reelin; dendrite; knock-in mouse; neuronal migration; proteolysis