Structure and function of a novel population of regenerating ependymal cells

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PROJECT SUMMARY The laboratory has identified a novel type of ependymal cell (E2) that has two long cilia anchored by two basal bodies that are 30-100 fold larger than those in other cells (Mirzadeh et al. 2008, 2017). E2 cells are found in strategic locations of the ventricular system, next to Neural Stem Cells (NSCs) in the walls of the lateral ventricle and in regions of the third and fourth ventricle critical to feeding and glucose regulation, circadian rhythms, consciousness, alertness and sleep (Mirzadeh et al. 2017). Interestingly, E2-like cells have been also observed in ependymomas, suggesting a link to proliferating progenitors and cancer (Alfaro-Cervelló et al. 2015; Ho, Caccamo, and Garcia 1994). E2 cells' genetic profile, the composition and organization of their unique cilia and basal bodies, their developmental origin, their regenerative capacity, and their function are not known. Ependymal (E) cells remain one of the least understood glial cell types in the brain, yet these cells are involved in functions that are essential for proper brain function. Multiciliated ependymal (E1) cells, through the coordinated beating of their ~50 motile cilia, contribute to cerebrospinal fluid (CSF) flow, and are required to prevent hydrocephalus (Jiménez et al. 2014; Ohata and Alvarez-Buylla 2016; Banizs et al. 2005). In the lateral ventricles, E cells contribute to the regulation of adult neural stem cells (NSCs) and neuronal migration in the largest germinal zone of the adult brain: the ventricular-subventricular zone (V-SVZ). How E cells sense and transmit CSF signals to this germinal niche remains unknown. It is unlikely that E2 cells through their two cilia contribute significantly to CSF flow. Instead, we propose that E2 cilia and basal body could play a key role in the detection of CSF signals. Their location at the interface between the CSF and important brain regions strongly suggests they have pivotal, as-yet unidentified, roles in brain function. Surprisingly, preliminary data indicate that the lateral ventricle E2 cells are relatively short-lived, decrease in number with age, and are constantly regenerated in adult mice. We propose to: 1) characterize E2 cells and their cilia and basal bodies using single cell gene expression analysis, electron and ultra-high resolution microscopy; 2) determine the development and adult population dynamics of E2 cells, and identify the progenitor cells giving rise to new E2 cells in the adult (preliminary evidence suggests that E2 cells are derived from adult NSCs); and 3) investigate whether E2 cell cilia signaling modulates adult stem cell niche function, using conditional deletion of a key cilia signaling molecule enriched in E2 cells. This new knowledge will be essential to decipher the function of E2 cells in the adult V-SVZ. In addition, molecular markers and signaling pathways identified in E2 cells could help understand the cell of origin and growth control of some ependymomas. Given the presence of E2 cells in the third and fourth ventricles, and central canal, next to regions of great functional importance, this new understanding will also help studies of E cell function throughout the brain.