Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
J Neurosci. 2020 May 6;40(19):3862-3879. doi: 10.1523/JNEUROSCI.1520-19.2020. Epub 2020 Apr 14.
Hydrocephalus is a pathologic condition associated with various brain diseases, including Alzheimer's disease (AD). Dysfunctional ependymal cells (EpCs) are believed to contribute to the development of hydrocephalus. It is thus of interest to investigate EpCs' development and function. Here, we report that vacuolar protein sorting-associated protein 35 (VPS35) is critical for EpC differentiation, ciliogenesis, and survival, and thus preventing neonatal hydrocephalus. VPS35 is abundantly expressed in EpCs. Mice with conditional knock-out (cKO) of Vps35 in embryonic (Vps35 and Vps35) or postnatal (Vps35) EpC progenitors exhibit enlarged lateral ventricles (LVs) and hydrocephalus-like pathology. Further studies reveal marked reductions in EpCs and their cilia in both Vps35 and Vps35 mutant mice. The reduced EpCs appear to be due to impairments in EpC differentiation and survival. Additionally, both Vps35 and Vps35 neonatal pups exhibit increased cell proliferation and death largely in a region close to LV-EpCs. Many microglia close to the mutant LV-EpC region become activated. Depletion of the microglia by PLX3397, an antagonist of colony-stimulating factor 1 receptor (CSF1R), restores LV-EpCs and diminishes the pathology of neonatal hydrocephalus in Vps35 mice. Taken together, these observations suggest unrecognized functions of Vps35 in EpC differentiation, ciliogenesis, and survival in neonatal LV, and reveal pathologic roles of locally activated microglia in EpC homeostasis and hydrocephalus development. This study reports critical functions of vacuolar protein sorting-associated protein 35 (VPS35) not only in promoting ependymal cell (EpC) differentiation, ciliogenesis, and survival, but also in preventing local microglial activation. The dysfunctional EpCs and activated microglia are likely to induce hydrocephalus.
脑积水是一种与多种脑部疾病相关的病理状态，包括阿尔茨海默病（AD）。功能失调的室管膜细胞（EpCs）被认为有助于脑积水的发展。因此，研究 EpCs 的发育和功能很有意义。在这里，我们报告液泡分选相关蛋白 35（VPS35）对于 EpC 分化、纤毛发生和存活至关重要，并能防止新生儿脑积水。VPS35 在 EpCs 中大量表达。胚胎期（Vps35 和 Vps35）或出生后（Vps35）条件性敲除（cKO）Vps35 的 EpC 祖细胞的小鼠表现出侧脑室（LV）扩大和类似脑积水的病理。进一步的研究表明，Vps35 和 Vps35 突变小鼠的 EpCs 和纤毛明显减少。减少的 EpCs 似乎是由于 EpC 分化和存活受损所致。此外，Vps35 和 Vps35 新生小鼠均表现出细胞增殖和死亡增加，主要发生在靠近 LV-EpCs 的区域。许多靠近突变 LV-EpC 区域的小胶质细胞被激活。PLX3397（集落刺激因子 1 受体（CSF1R）拮抗剂）耗尽小胶质细胞可恢复 LV-EpC，并减轻 Vps35 小鼠的新生儿脑积水病理。总之，这些观察结果表明 Vps35 在新生儿 LV 中 EpC 分化、纤毛发生和存活方面具有未被认识的功能，并揭示了局部激活的小胶质细胞在 EpC 动态平衡和脑积水发展中的病理作用。本研究报道了液泡分选相关蛋白 35（VPS35）的关键功能，不仅能促进室管膜细胞（EpC）分化、纤毛发生和存活，还能防止局部小胶质细胞激活。功能失调的 EpCs 和激活的小胶质细胞可能会引发脑积水。
