1. Academic Validation
  2. Ependymal Vps35 Promotes Ependymal Cell Differentiation and Survival, Suppresses Microglial Activation, and Prevents Neonatal Hydrocephalus

Ependymal Vps35 Promotes Ependymal Cell Differentiation and Survival, Suppresses Microglial Activation, and Prevents Neonatal Hydrocephalus

  • J Neurosci. 2020 May 6;40(19):3862-3879. doi: 10.1523/JNEUROSCI.1520-19.2020.
Kong-Yan Wu 1 Fu-Lei Tang 2 Daehoon Lee 1 Yang Zhao 1 3 Hyunjin Song 2 Xiao-Juan Zhu 3 Lin Mei 1 2 4 Wen-Cheng Xiong 5 2 4
Affiliations

Affiliations

  • 1 Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106.
  • 2 Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
  • 3 Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Cytology and Genetics, Northeast Normal University, Changchun, Jilin 130024, China.
  • 4 Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio 44106.
  • 5 Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 wen-cheng.xiong@case.edu.
Abstract

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 (Vps35GFAP-Cre and Vps35Emx1-Cre) or postnatal (Vps35Foxj1-CreER) EpC progenitors exhibit enlarged lateral ventricles (LVs) and hydrocephalus-like pathology. Further studies reveal marked reductions in EpCs and their cilia in both Vps35GFAP-Cre and Vps35Foxj1-CreER mutant mice. The reduced EpCs appear to be due to impairments in EpC differentiation and survival. Additionally, both Vps35GFAP-Cre and Vps35Foxj1-CreER 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 Vps35Foxj1-CreER 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.SIGNIFICANCE STATEMENT 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.

Keywords

VPS35; ciliogenesis; ependymal cells; hydrocephalus; microglia.

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