Forebrain-specific deficiency of the GTPase CRAG/Centaurin-γ3 leads to immature dentate gyri and hyperactivity in mice

Shun Nagashima, Naoki Ito, Reiki Kobayashi, Isshin Shiiba, Hiroki Shimura, Toshifumi Fukuda, Hideo Hagihara, Tsuyoshi Miyakawa, Ryoko Inatome, Shigeru Yanagi

Research output: Contribution to journalArticlepeer-review

Abstract

Mouse models of various neuropsychiatric disorders, such as schizophrenia, often display an immature dentate gyrus, characterized by increased numbers of immature neurons and neuronal progenitors and a dearth of mature neurons. We previously demonstrated that the CRMP5-associated GTPase (CRAG), a short splice variant of Centaurin-γ3/AGAP3, is highly expressed in the dentate gyrus. CRAG promotes cell survival and antioxidant defense by inducing the activation of serum response factors at promyelocytic leukemia protein bodies, which are nuclear stress-responsive domains, during neuronal development. However, the physiological role of CRAG in neuronal development remains unknown. Here, we analyzed the role of CRAG using dorsal forebrain-specific CRAG/Centaurin-γ3 knockout mice. The mice revealed maturational abnormality of the hippocampal granule cells, including increased doublecortin-positive immature neurons and decreased calbindin-positive mature neurons, a typical phenotype of immature dentate gyri. Furthermore, the mice displayed hyperactivity in the open-field test, a common measure of exploratory behavior, suggesting that these mice may serve as a novel model for neuropsychiatric disorder associated with hyperactivity. Thus, we conclude that CRAG is required for the maturation of neurons in the dentate gyrus, raising the possibility that its deficiency might promote the development of psychiatric disorders in humans.

Original languageEnglish
Article number100620
JournalJournal of Biological Chemistry
Volume296
DOIs
Publication statusPublished - 01-01-2021

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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