Deciphering the spatial-temporal transcriptional landscape of human hypothalamus development

Zhou, Xin; Lü, Yongtao; Zhao, Fangqi; Dong, Ji; Wei-hua, MA; Zhong, Shaobo; Wang, Mengdi; Wang, Bosong; Zhao, Yu‐Qing; Shi, Yingchao; Ma, Qiang; Tian, Lu; Zhang, Jun; Wang, Xiaoqun; Wu, Qian

doi:10.1016/j.stem.2021.11.009

Cited by 28 publications

(52 citation statements)

References 89 publications

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“…Notably, certain nuclei appeared to mature at different rates. Distinct developmental dynamics among hypothalamic nuclei are consistent with previous reports using immunohistochemistry (33) as well as a recently published single-cell transcriptomics study of the human prenatal hypothalamus covering GW7 -20 (34).…”

Section: Discussionsupporting

confidence: 91%

“…We detected 170 transcriptionally distinct neuronal populations in the adult hypothalamus, 147 of which could be mapped to specific nuclei. These numbers are within the range of detected neuronal cell types by scRNA-seq at postnatal timepoints in mice (4)(5)(6)(7)(8)(9)(10)(11), and more than three times the number of distinct populations described previously for the human hypothalamus (34). The increased resolution of our dataset can be attributed to adult timepoints with more mature neurons.…”

Section: Discussionsupporting

confidence: 79%

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Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the human hypothalamus

Herb

Glover

Bhaduri

et al. 2021

Preprint

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The hypothalamus is critically important for regulating most autonomic, metabolic, and behavioral functions essential for life and species propagation, yet a comprehensive understanding of neuronal subtypes and their development in the human brain is lacking. Here, we characterized the prenatal human hypothalamus by sequencing the transcriptomes of 45,574 single-cells from 12 embryos, spanning gestational weeks 4 through 25. These cells describe a temporal trajectory from proliferative stem cell populations to maturing neurons and glia, including 38 distinct excitatory and inhibitory neuronal subtypes. Merging these data with paired samples from the cortex and ganglionic eminences (GE) revealed two distinct neurogenesis pathways, one shared between GE and hypothalamus and a second unique to cortex. Gene regulatory network modeling predicted that these distinct maturation trajectories involve the activation of region- and cell type-specific transcription factor networks. These results provide the first comprehensive transcriptomic view of human hypothalamus development at cellular resolution.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 79%

Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the human hypothalamus

Herb

Glover

Bhaduri

et al. 2021

Preprint

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“…We next set out to characterize the various hypothalamus cell populations using our scRNA-seq data. Utilizing differential expressed genes and celltype specific markers curated from literature and previous studies in hypothalamus, we first determined the various cell-type clusters [29][30][31][32][33][34][35][36][37][38][39][40][41] . We identified 37 distinctive cell populations, including 34 previously-described cell-types and four specialized neurons that were not described in previous studies.…”

Section: Combined Sc-rna and Atac Profiling Of The Mouse Hypothalamusmentioning

confidence: 99%

Integrative single-cell characterization of hypothalamus sex-differential and obesity-associated genes and regulatory elements

Nguyen

Chan

Cintron

et al. 2022

Preprint

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Over 500 noncoding genomic loci are associated with obesity. The majority of these loci reside near genes that are expressed in the hypothalamus in specific neuronal subpopulations that regulate food intake, hindering the ability to identify and functionally characterize them. Here, we carried out integrative single-cell analysis (RNA/ATAC-seq) on both mouse and human male and female hypothalamus to characterize genes and regulatory elements in specific cell subpopulations. Utilizing both transcriptome and regulome data, we identify over 30 different neuronal and non-neuronal cell subpopulations and a shared core of transcription factors that regulate cell cluster-specific genes between mice and humans. We characterize several sex-specific differentially expressed genes and the regulatory elements that control them in specific cell subpopulations. Overlapping cell-specific scATAC peaks with obesity-associated GWAS variants, identifies potential obesity-associated regulatory elements. Using reporter assays and CRISPR editing, we show that many of these sequences, including the top obesity-associated loci (FTO and MC4R), are functional enhancers whose activity is altered due to the obesity-associated variant and regulate known obesity genes. Combined, our work provides a catalog of genes and regulatory elements in hypothalamus cell subpopulations and uses obesity to showcase how integrative single-cell sequencing can identify functional variants associated with hypothalamus-related phenotypes.

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“…ScRNA-Seq analyses and large-scale expression studies in mouse have profiled and spatially mapped major hypothalamic neuronal subtypes (Kim et al, 2022, Lee et al, 2018, Romanov et al, 2020, Shimogori et al, 2010), and in combination with classic genetic studies (Aslanpour et al, 2020, Bedont et al, 2014, Chen et al, 2020, Liu et al, 2015, Lu et al, 2013, Newman et al, 2018a, Newman et al, 2018b, Pak et al, 2014, Salvatierra et al, 2014) have identified key molecular regulators of hypothalamic neurogenesis and gliogenesis. More recently, scRNA-Seq studies covering early hypothalamic neurogenesis in embryonic chick, mouse, and human have identified markers of the major hypothalamic progenitor subtypes, and provided insights into the molecular mechanisms controlling their specification (Kim et al, 2022, Kim et al, 2020, Romanov et al, 2020, Zhou et al, 2022, Zhou et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

A neuroepithelial wave of BMP signalling drives anteroposterior specification of the tuberal hypothalamus

Placzek

Chinnaiya

Burbridge

et al. 2022

Preprint

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The tuberal hypothalamus houses several major hypothalamic nuclei, dozens of transcriptionally distinct cell types, and clinically relevant cell populations implicated in obesity and related metabolic disorders. Building on recent advances in the field, here we draw upon transcriptional, signalling, and fate mapping analyses of chicken embryos and neuroepithelial explants to analyze tuberal hypothalamic development. We show that a wave of BMP signalling sweeps through early floor plate-like progenitors overlying prospective Rathkes pouch as they track anteriorly. The timing of BMP signalling correlates with cell fate, with anterior tuberal specification complete by Hamilton-Hamburger (HH) stage 10 but posterior tuberal progenitors requiring BMPs after this point. scRNA-Seq profiling of FGF10-expressing cells, a proxy for cells with active BMP signalling, through HH8-21 reveals transcriptional differences that may underlie their differing response to BMPs, and the switch from neuroepithelial progenitors to stem-like radial glial cells. This study provides an integrated account of the development of the tuberal hypothalamus.

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Deciphering the spatial-temporal transcriptional landscape of human hypothalamus development

Cited by 28 publications

References 89 publications

Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the human hypothalamus

Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the human hypothalamus

Integrative single-cell characterization of hypothalamus sex-differential and obesity-associated genes and regulatory elements

A neuroepithelial wave of BMP signalling drives anteroposterior specification of the tuberal hypothalamus

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