Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan; Laboratory of Molecular Biochemistry, Department of Life Science, Faculty of Science, Gakushuin University, Toshima-ku, Tokyo, Japan.
J Biol Chem. 2021 Jan-Jun;296:100620. doi: 10.1016/j.jbc.2021.100620. Epub 2021 Mar 31.
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.
各种神经精神疾病的小鼠模型，如精神分裂症，通常表现出未成熟的齿状回，其特征是未成熟神经元和神经元祖细胞数量增加，成熟神经元数量减少。我们之前证明，与 CRMP5 相关的 GTP 酶（CRAG），即 Centaurin-γ3/AGAP3 的短剪接变体，在齿状回中高度表达。CRAG 通过在成髓细胞瘤蛋白体（核应激反应域）诱导血清反应因子的激活，促进细胞存活和抗氧化防御，在神经元发育过程中发挥作用。然而，CRAG 在神经元发育中的生理作用尚不清楚。在这里，我们使用背侧前脑特异性 CRAG/Centaurin-γ3 敲除小鼠分析了 CRAG 的作用。这些小鼠表现出海马颗粒细胞的成熟异常，包括增加的双皮质素阳性未成熟神经元和减少的钙结合蛋白阳性成熟神经元，这是未成熟齿状回的典型表型。此外，这些小鼠在旷场测试中表现出过度活跃，这是探索性行为的常用测量方法，表明这些小鼠可能作为与过度活跃相关的神经精神疾病的新型模型。因此，我们得出结论，CRAG 是齿状回神经元成熟所必需的，这提示其缺乏可能促进人类精神疾病的发展。
