Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu, 501-1196, Japan.
Neurochem Res. 2019 Feb;44(2):374-387. doi: 10.1007/s11064-018-2684-7. Epub 2018 Nov 20.
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.
神经生长因子诱导（VGF）是一种神经营养因子诱导的神经肽前体。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，过表达 VGF 的小鼠表现出类似精神分裂症的行为和较小的脑重。脑发育异常是精神疾病的一个原因。对脑发育的研究对于发现精神障碍的发病机制很重要。在本研究中，我们研究了 VGF 对小脑发育的作用。我们通过尼氏染色对成年和出生后第 3 天的小鼠小脑切片进行组织学分析。为了研究小脑发育，我们用未成熟和成熟颗粒细胞标志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 blot 检查 MAPK、Wnt 和 sonic hedgehog 信号。最后，我们使用成年小鼠进行转棒和足迹测试，以研究运动功能。过表达 VGF 的成年小鼠小脑矢状切片面积较小。在出生后第 3 天的小鼠中，过表达 VGF 的小鼠整个小脑和外颗粒层的小脑矢状切片面积减少，成熟颗粒细胞数量减少。此外，过表达 VGF 的小鼠增殖性颗粒细胞前体细胞数量减少。过表达 VGF 的出生后第 3 天小鼠小脑的 Trk 和 Erk1 磷酸化增加。成年过表达 VGF 的小鼠表现出运动障碍。综上所述，这些发现表明 VGF 通过促进 MAPK 信号转导和成年期的运动功能参与小脑颗粒细胞的发育。
