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Control of neurogenic competence in mammalian hypothalamic tanycytes [ATAC-seq]

ABSTRACT: Hypothalamic tanycytes, radial glial cells that share many features with neuronal progenitors, can generate small numbers of neurons in the postnatal hypothalamus, but the identity of these neurons and the molecular mechanisms that control tanycyte-derived neurogenesis are unknown. We report that tanycyte-specific disruption of the NFI family of transcription factors (Nfia/b/x) stimulates proliferation and tanycyte-derived neurogenesis. Single-cell RNA- and ATAC-Seq analysis reveals that NFI factors repress Shh and Wnt signaling in tanycytes, and small molecule inhibition of these pathways blocks proliferation and tanycyte-derived neurogenesis in Nfia/b/x-deficient mice. We show that Nfia/b/x-deficient tanycytes give rise to multiple mediobasal hypothalamic neuronal subtypes that can mature, integrate into hypothalamic circuitry, and selectively respond to changes in internal states. These findings identify molecular mechanisms controlling tanycyte-derived neurogenesis that can potentially be targeted to selectively remodel hypothalamic neural circuitry controlling homeostatic physiological processes.

ORGANISM(S): Mus musculus

PROVIDER: GSE160375 | GEO | 2020/10/30

REPOSITORIES: GEO

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Project description:Background: Neuronal and glial differentiation in the murine hypothalamus is not complete at birth, but continues over the first two weeks postnatally. Nutritional status and Leptin deficiency can influence the maturation of neuronal projections and glial patterns, and hypothalamic gliosis occurs in mouse models of obesity. Gnasxl constitutes an alternative transcript of the genomically imprinted Gnas locus and encodes a variant of the signalling protein GÎ±s, termed XLÎ±s, which is expressed in defined areas of the hypothalamus. Gnasxl-deficient mice show postnatal growth retardation and undernutrition, while surviving adults remain lean and hypermetabolic with increased sympathetic nervous system (SNS) activity. Effects of this knock-out on the hypothalamic neural network have not yet been investigated. Results: RNAseq analysis for gene expression changes in hypothalami of Gnasxl-deficient mice indicated Glial fibrillary acid protein (Gfap) expression to be significantly down-regulated in adult samples. Histological analysis confirmed a reduction in Gfap-positive glial cell numbers specifically in the hypothalamus. This reduction was observed in adult tissue samples, whereas no difference was found in hypothalami of postnatal stages, indicating an adaptation in adult Gnasxl-deficient mice to their earlier growth phenotype and hypermetabolism. Especially noticeable was a loss of many Gfap-positive Î±-tanycytes and their processes, which form part of the ependymal layer that lines the medial and dorsal regions of the 3rd ventricle, while Î²-tanycytes along the median eminence (ME) and infundibular recesses appeared unaffected. This was accompanied by local reductions in Vimentin and Nestin expression. Hypothalamic RNA levels of glial solute transporters were, unchanged, indicating a potential compensatory up-regulation in the remaining astrocytes and tanycytes. Conclusion: Gnasxl deficiency does not directly affect glial development in the hypothalamus, since it is expressed in neurons, and Gfap-positive astrocytes and tanycytes appear normal during early postnatal stages. The loss of Gfap-expressing cells in adult hypothalami appears to be a consequence of the postnatal undernutrition, hypoglycaemia and continued hypermetabolism and leanness of Gnasxl-deficient mice, which contrasts with gliosis observed in obese mouse models. Since Î±-tanycytes also function as adult neural progenitor cells, these findings might indicate further developmental abnormalities in hypothalamic formations of Gnasxl-deficient mice, potentially including neuronal composition and projections. 6 wildtype and 6 Gnasxlm+/p- RNA isolates were used, which were pooled in pairs in equal concentrations prior to rRNA removal using the RiboMinus kit (Life Technologies)

Project description:The ependyma lining the third ventricle (3V) in the mediobasal hypothalamus is recognized as a critical player in controlling energy balance and glucose homeostasis. Its molecularly distinct cell types, namely diverse tanycyte subpopulations and typical ependymal cells, confer a high functional heterogeneity and plasticity to this complex ependymal system, but the molecular mechanisms governing its features, especially in the context of metabolic regulation, are still not fully understood.Here, 5481 hypothalamic ependymocytes were cataloged using FACS-assisted single-cell RNA sequencing from fed, 12h-fasted, and 24h-fasted adult male mice. We first observed the limitations of using standard clustering analysis to characterize the different ependymal cell subpopulations lining the 3V. Indeed, while typical ependymal cells and β2-tanycytes are sharply defined at the molecular level using this approach, other subpopulations (i.e., β1- and α-tanycytes) display fuzzy boundaries and very few specific markers. Moreover, 12h- and 24h-fasting dynamically modulate gene expression, increasing tanycyte subgroup heterogeneity. To better analyze the dynamic changes in tanycytes’ gene expression profile, we implemented a pseudospatial analysis based on 3V neuroanatomical distribution, which we validated using in-situ hybridization, immunohistochemistry, and histologic staining. This approach improved the characterization of tanycyte markers, refining our knowledge of specific versus shared features and the segregation of subgroup-specific versus general tanycyte functions. Importantly, we showed that fasting dynamically shifts patterns in gene expression and transcription activity along the 3V, inducing metabolic and functional switches in tanycyte subpopulations, particularly regarding lipid metabolism. Additionally, numerous functions related to tanycyte-neuron and tanycyte-synapse interactions, notably through Nrxn1 expression, present a functional dorso→ventral shift towards the arcuate nucleus during fasting. Altogether, this data shows that changes in energy status lead to a spatial redistribution of distinct cell type-specific responses along the 3V and gives new insights into molecular and functional diversity and plasticity within the tanycyte population.

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Control of neurogenic competence in mammalian hypothalamic tanycytes [ATAC-seq]

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