Impaired cerebellar development in mice overexpressing VGF
Impaired cerebellar development in mice overexpressing VGF
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过度表达 VGF 的小鼠小脑发育受损
DOI：
10.1007/s11064-018-2684-7
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Nakamura S and Hara H.
中科院分区：
文献类型：
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作者：
Mizoguchi T;Shimazawa M Ohuchi K;Kuse Y;Nakamura S and Hara H.
神经生长因子诱导因子（VGF）是脑源性神经营养因子和神经生长因子共同诱导的神经肽前体。精神分裂症患者的前额叶皮层和脑脊液中VGF增加。在我们之前的研究中，VEGF过度表达的小鼠表现出精神分裂症样行为和较小的脑重量。脑发育异常是导致精神疾病的原因之一。脑发育研究对于发现精神障碍的发病机制具有重要意义。在本研究中，我们探讨了VGF在小脑发育中的作用。我们用尼氏染色法对成年和出生后3天的小鼠小脑切片进行了组织学分析。为了研究小脑的发育，我们用未成熟和成熟颗粒细胞标记物的抗体进行免疫染色。为了了解这些组织学变化的机制，我们通过Western印迹检测了MAPK、Wnt和音刺猬信号。最后，我们使用成年小鼠进行旋转棒和足迹测试来研究运动功能。VEGF过表达的成年小鼠小脑矢状截面积较小。在出生后第3天的小鼠，小脑矢状截面面积减少，整个小脑和外部颗粒层和成熟颗粒细胞的数量减少，发现在VEGF过表达的小鼠。此外，增殖颗粒细胞前体的数量在VEGF过表达小鼠中较低。Trk和Erk1的磷酸化在出生后第3天VEGF过表达小鼠的小脑中增加。成年VEGF过表达小鼠表现出运动障碍。总之，这些发现暗示VGF通过促进MAPK信号传导和成年阶段的运动功能参与小脑颗粒细胞的发育。
VGF nerve growth factor inducible (VGF) is a neuropeptide precursor induced by brain-derived neurotrophic factor and nerve growth factor. VGF is increased in the prefrontal cortex and cerebrospinal fluid in schizophrenia patients. In our previous study, VGF-overexpressing mice exhibited schizophrenia-like behaviors and smaller brain weights. Brain developmental abnormality is one cause of mental illness. Research on brain development is important for discovery of pathogenesis of mental disorders. In the present study, we investigated the role of VGF on cerebellar development. We performed a histological analysis with cerebellar sections of adult and postnatal day 3 mice by Nissl staining. To investigate cerebellar development, we performed immunostaining with antibodies of immature and mature granule cell markers. To understand the mechanism underlying these histological changes, we examined MAPK, Wnt, and sonic hedgehog signaling by Western blot. Finally, we performed rotarod and footprint tests using adult mice to investigate motor function. VGF-overexpressing adult mice exhibited smaller cerebellar sagittal section area. In postnatal day 3 mice, a cerebellar sagittal section area reduction of the whole cerebellum and external granule layer and a decrease in the number of mature granule cells were found in VGF-overexpressing mice. Additionally, the number of proliferative granule cell precursors was lower in VGF-overexpressing mice. Phosphorylation of Trk and Erk1 were increased in the cerebellum of postnatal day 3 VGF-overexpressing mice. Adult VGF-overexpressing mice exhibited motor disability. All together, these findings implicate VGF in the development of cerebellar granule cells via promoting MAPK signaling and motor function in the adult stage.