The Identification and Characterization of Tanycyte Stem Cells

The formation of the brain is perhaps one of the most remarkable processes in biology, and at its core, is orchestrated by neural progenitors that give rise to a wide array of cell types in a precise, temporally coordinated manner. A century-long effort to characterize these neural progenitor cells, from early histological studies to current single-cell transcriptional profiling, has converged on a model of neurodevelopment based largely on processes occurring in the embryonic cortex thought to be broadly applicable across the brain. This model states that neuroepithelial cells (NEPs) lining the early neural tube eventually transition into radial glial cells (RGCs) within the nascent ventricular zone, which then give rise to nearly all the neurons and macroglia in the brain. However, the hypothalamus is an evolutionarily ancient brain region with a characteristic nuclear organization and striking environmental sensitivity, which are features that may not be accounted for in the present cortex-focused model. Here, I study whether the hypothalamus employs unique developmental programs. In particular, I ask whether tanycytes, a radial glia-like population with diverse metabolic functions and putative postnatal neural stem capacity, reside along the embryonic hypothalamic third ventricle (3V) and contribute to regional hypothalamic neurogenesis and gliogenesis in a manner that is sensitive to the maternal environment. Morphological, spatial, and transcriptomic analyses of hypothalamic ventricular cells revealed a novel population of NEP-derived, caudally located, tanycyte-like progenitors that formed a parallel lineage to hypothalamic RGCs; based on transcriptional similarities to postnatal tanycytes, we termed these cells tanycyte stem cells (TSCs). Comparisons of TSC and lamprey ependymoglia gene expression signatures suggested that the TSC lineage is evolutionarily conserved from a common vertebrate ancestor. Lineage tracing and diphtheria toxin-mediated ablation of a Troy-expressing subpopulation of TSCs revealed that these cells are necessary to give rise to neurons and glia in the mammillary region of the hypothalamus. Finally, these TSCs were robustly sensitive to maternal metabolic state, modulating neurogenic output in response to a maternal high-fat diet challenge in mice, and mounting a similar response in humans based on single-nucleus RNA sequencing data of human fetal hypothalamic tissue derived from either lean or obese pregnancies. Together, this work identifies the functional role of a novel region-specific, non-RGC progenitor population, and raises new concepts about neural progenitor heterogeneity, evolution, and therapeutic relevance.