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Pseudotemporal Ordering of Single Cells Reveals Metabolic Control of Postnatal ? Cell Proliferation.

ABSTRACT: Pancreatic ? cell mass for appropriate blood glucose control is established during early postnatal life. ? cell proliferative capacity declines postnatally, but the extrinsic cues and intracellular signals that cause this decline remain unknown. To obtain a high-resolution map of ? cell transcriptome dynamics after birth, we generated single-cell RNA-seq data of ? cells from multiple postnatal time points and ordered cells based on transcriptional similarity using a new analytical tool. This analysis captured signatures of immature, proliferative ? cells and established high expression of amino acid metabolic, mitochondrial, and Srf/Jun/Fos transcription factor genes as their hallmark feature. Experimental validation revealed high metabolic activity in immature ? cells and a role for reactive oxygen species and Srf/Jun/Fos transcription factors in driving postnatal ? cell proliferation and mass expansion. Our work provides the first high-resolution molecular characterization of state changes in postnatal ? cells and paves the way for the identification of novel therapeutic targets to stimulate ? cell regeneration.

SUBMITTER: Zeng C

PROVIDER: S-EPMC5501713 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Pseudotemporal Ordering of Single Cells Reveals Metabolic Control of Postnatal β Cell Proliferation.

Zeng Chun C Mulas Francesca F Sui Yinghui Y Guan Tiffany T Miller Nathanael N Tan Yuliang Y Liu Fenfen F Jin Wen W Carrano Andrea C AC Huising Mark O MO Shirihai Orian S OS Yeo Gene W GW Sander Maike M

Cell metabolism 20170501 5

Pancreatic β cell mass for appropriate blood glucose control is established during early postnatal life. β cell proliferative capacity declines postnatally, but the extrinsic cues and intracellular signals that cause this decline remain unknown. To obtain a high-resolution map of β cell transcriptome dynamics after birth, we generated single-cell RNA-seq data of β cells from multiple postnatal time points and ordered cells based on transcriptional similarity using a new analytical tool. This ana ...[more]

PMID: 28467932

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Project description:BackgroundCerebellar neurogenesis involves the generation of large numbers of cerebellar granule neurons (GNs) throughout development of the cerebellum, a process that involves tight regulation of proliferation and differentiation of granule neuron progenitors (GNPs). A number of transcriptional regulators, including Math1, and the signaling molecules Wnt and Shh have been shown to have important roles in GNP proliferation and differentiation, and deregulation of granule cell development has been reported to be associated with the pathogenesis of medulloblastoma. While the progenitor/differentiation states of cerebellar granule cells have been broadly investigated, a more detailed association between developmental differentiation programs and spatial gene expression patterns, and how these lead to differential generation of distinct types of medulloblastoma remains poorly understood. Here, we provide a comparative single-cell spatial transcriptomics analysis to better understand the similarities and differences between developing granule and medulloblastoma cells.ResultsTo acquire an enhanced understanding of the precise cellular states of developing cerebellar granule cells, we performed single-cell RNA sequencing of 24,919 murine cerebellar cells from granule neuron-specific reporter mice (Math1-GFP; Dcx-DsRed mice). Our single-cell analysis revealed that there are four major states of developing cerebellar granule cells, including two subsets of granule progenitors and two subsets of differentiating/differentiated granule neurons. Further spatial transcriptomics technology enabled visualization of their spatial locations in cerebellum. In addition, we performed single-cell RNA sequencing of 18,372 cells from Patched+/- mutant mice and found that the transformed granule cells in medulloblastoma closely resembled developing granule neurons of varying differentiation states. However, transformed granule neuron progenitors in medulloblastoma exhibit noticeably less tendency to differentiate compared with cells in normal development.ConclusionIn sum, our study revealed the cellular and spatial organization of the detailed states of cerebellar granule cells and provided direct evidence for the similarities and discrepancies between normal cerebellar development and tumorigenesis.

Dataset Information

Pseudotemporal Ordering of Single Cells Reveals Metabolic Control of Postnatal ? Cell Proliferation.

Publications

Pseudotemporal Ordering of Single Cells Reveals Metabolic Control of Postnatal β Cell Proliferation.

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