Importance of reelin C-terminal region in the development and maintenance of the postnatal cerebral cortex and its regulation by specific proteolysis

Takao Kohno, Takao Honda, Ken Ichiro Kubo, Yoshimi Nakano, Ayaka Tsuchiya, Tatsuro Murakami, Hideyuki Banno, Kazunori Nakajima, Mitsuharu Hattori

Research output: Contribution to journalArticle

37 Citations (Scopus)

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 theMZrequire 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.

Original languageEnglish
Pages (from-to)4776-4787
Number of pages12
JournalJournal of Neuroscience
Volume35
Issue number11
DOIs
Publication statusPublished - 2015

Keywords

  • Dab1
  • Dendrite
  • Knock-in mouse
  • Neuronal migration
  • Proteolysis
  • Reelin

ASJC Scopus subject areas

  • Neuroscience(all)

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