Investigating Functional Ependymal Cell Heterogeneity in the Ventricular System

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Project Summary/Abstract: The brain is made up of highly specialized neurons and glia, organized spatially into distinct functional units, interconnected to perform some of the most complex computations in nature. To date, cutting-edge molecular and genetic tools have been applied overwhelmingly to the study of neural structure and function. Less well understood are glial cells, despite the fact that radial glia generate all neurons in the central nervous system during embryonic development. Adult neural stem cells (aNSCs) share many features of radial glia and astrocytes, and in mice give rise to new neurons throughout life. aNSCs are present in the lateral walls of the lateral ventricles, and sit in complex cellular niches that regulate many features of their activity. We and others have previously found that the neurogenic potential of aNSCs depends on the aNSC’s position along the two- dimensional surface of the ventricular wall. Dorsal aNSCs generate superficial-layer granular cells for the olfactory bulb, while ventral aNSCs produce deep-layer granular cells. Adult NSC neurogenic potential is cell- intrinsic, as heterotopically transplanted cells produce neurons consistent with their original position. However, instructive niche cell signaling may also be regionally defined, as recent work demonstrates spatially selective aNSC activation directly or indirectly by projection neurons in response to feeding behavior. Given the widespread interest in stem cell therapies for brain repair, a critical gap in knowledge is the lack of mechanistic insight into molecular determinants of aNSC neurogenic potential and of neurogenic niche regionalization. I hypothesize that regionally-restricted transcriptional signatures define aNSC neurogenic potential, and complementary signatures in niche glia underlie region-specific extrinsic control of adult neurogenesis. In this proposal, I put forward three orthogonal Aims that span the K99 and R00 phases of the award. In the first two Aims completed largely in the K99 phase, I use single cell sequencing to identify dorsal and ventral clusters of aNSCs and niche glia, and mouse genetics to assess signature-driving gene contributions to regional identity. The R00 phase is mainly accomplished in Aim 3, where I build on my existing preliminary single cell RNA- sequencing analyses to gain mechanistic insight into functional heterogeneity among ependymal cells throughout the ventricular system. Together, these data will provide a foundational understanding of neurogenic niche signaling dynamics that together drive neurogenesis, and creates a new avenue of exploration to understand the diverse roles of ependymal cells at the brain/cerebral spinal fluid interface.