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Decoding the origin of neuronal diversity in hypothalamus by single-cell RNA-seq

ABSTRACT: The hypothalamus is one of the most complex brain structures whose development involves a plastic process of neuronal fate specification. Progress has been made to decipher the gene regulatory programs that are responsible for hypothalamus development; however, the molecular developmetal trajectory of hyothalamus is largely unknown. To understand how pre- and postmitotic transcriptional programs interact and coordinate to endow neuronal cell subtypes with their characteristic properties during hypothalamic development, we performed single-cell RNA sequencing (scRNA-seq) on single cells derived from Rax+ hypothalamic neuroepithelium at four critical developmental points during hypothalamic development. Our single-cell analysis provides a developmental landscape of mouse hypothalamus. We show that while the fate of radial glial cells (RGCs) is predetermined before differentiation but lack spatial code to distinguish from each other, different clusters of intermediate progenitors (IPCs) emerge to display diversifying fates and subdivide hypothalamic primordium into distinct spatially-restricted progenitor domains. We further characterize the maturation dynamics of hypothalamic neurons and suggest that immature neurons could evolve into multiple peptidergic neuronal subtypes. Finally, we identify sets of transcription factors (TFs) serving as regulons to determine the fate of diverse GABAergic and Glutamatergic neurons in hypothalamus. Together, our study offers a single-cell transcriptional framework for the hypothalamus developmental trajectory and propose a cascade diversifying model to deconstruct the origin of neuronal diversity in hypothalamus.

ORGANISM(S): Mus musculus

PROVIDER: GSE151060 | GEO | 2021/08/05

REPOSITORIES: GEO

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Project description:Purpose: We aimed to reconstruct the development formation of cellular identities' heterogeneity in the hypothalamus with single-cell RNA sequencing. We planned to track branching process of neurogenesis and follow the formation of cell identities. Results: We integrate single-cell RNA-seq data on 51,199 cells of ectodermal origin, representing critical stages of pre- and postnatal hypothalamus development, supported by anatomical lineage reconstruction to show that bulk neurogenesis in the hypothalamus, dominated by Notch signalling and its interaction with Ascl1, persists until the neonatal period to produce molecularly distinct astrocytes, ependyma, tanycytes and 30 protoclusters of neurons. Alike in adults, the assignment of neurotransmitters and neuropeptides together with transcription factors as positional marks for each neuronal cluster is sufficient to establish the spatially-resolved taxonomy of hypothalamic neurons. By deducing gene regulatory networks, exemplified by hierarchical gene clusters driven by Onecut2/Onecut3 transcription factors for dopamine neurons, we resolve how neuronal lineages diverge into functionally non-overlapping endocrine subtypes. Dopamine neurons are used to illustrate molecular convergence with their shared neurotransmitter identity representing a mismatch to their molecular distances on multidimensional vector spaces. We demonstrate the existence of non-canonical chemotropic axes in the hypothalamus, particularly sequential ligand-receptor switching in the unexpectedly abundant Slit/Robo cassette. Slit2 is identified in ventricular ependymocytes and implicated in repulsing new-born neurons that sequentially express Robo1 and Robo2 receptors for migration and differentiation. Conclusions: Overall, our unbiased map of hypothalamic cell types and extracellular guidance cues uncovers molecular principles shaping the developmental architecture of the mammalian hypothalamus and rationalise how hypothalamic neuronal heterogeneity is transformed into a multimodal neural unit that retains a virtually infinite adaptive potential throughout life.

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Decoding the origin of neuronal diversity in hypothalamus by single-cell RNA-seq

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