An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome

Liu, S.; Ezran, C.; Wang, M. F. Z.; Li, Z.; The Tabula Microcebus Consortium,; Long, J. Z.; De Vlaminck, I.; Wang, S.; Kuo, C.; Epelbaum, J.; Terrien, J.; Krasnow, M. A.; Ferrell, J. E.

doi:10.1101/2021.12.13.472243

bioRxiv · 10.1101/2021.12.13.472243

An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome

Liu, S.·Ezran, C.·Wang, M. F. Z.·Li, Z.·The Tabula Microcebus Consortium,·Long, J. Z.·De Vlaminck, I.·Wang, S.·Kuo, C.·Epelbaum, J.·Terrien, J.·Krasnow, M. A.·Ferrell, J. E.

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Abstract

Hormones mediate long-range cell communication in multicellular organisms and play vital roles in normal physiology, metabolism, and health. Using the newly-completed organism-wide single cell transcriptional atlas of a non-human primate, the mouse lemur (Microcebus murinus), we have systematically identified hormone-producing and -target cells for 84 classes of hormones, and have created a browsable atlas for hormone signaling that reveals previously unreported sites of hormone regulation and species-specific rewiring. Hormone ligands and receptors exhibited cell-type-dependent, stereotypical expression patterns, and their transcriptional profiles faithfully classified the molecular cell type identities, despite their comprising less than 1% of the transcriptome. Cells of similar cell types further display stage, subtype or organ-dependent specification of hormonal signaling, reflecting the precise control of global hormonal regulation. By linking ligand-expressing cells to the cells expressing the corresponding receptor, we constructed an organism-wide map of the hormonal cell communication network. This network was remarkably densely and robustly connected and included a myriad of feedback circuits. Although it includes classical hierarchical circuits (e.g. pituitary [->] peripheral endocrine gland [->] diverse cell types), the hormonal network is overall highly distributed without obvious network hubs or axes. Cross-species comparisons among humans, lemurs, and mice suggest that the mouse lemur better models human hormonal signaling, than does the mouse. Hormonal genes show a higher evolutionary conservation between human and lemur vs. human and mouse at both the genomic level (orthology-mapping and sequence identity) and the transcriptional level (cell type expression patterns). This primate hormone atlas provides a powerful resource to facilitate discovery of regulation on an organism-wide scale and at single-cell resolution, complementing the single-site-focused strategy of classical endocrine studies. The network nature of hormone regulation and the principles discovered here further emphasize the importance of a systems approach to understanding hormone regulation.

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Liu, S., Ezran, C., Wang, M. F. Z., Li, Z., The Tabula Microcebus Consortium,, Long, J. Z., De Vlaminck, I., Wang, S., Kuo, C., Epelbaum, J., Terrien, J., Krasnow, M. A., Ferrell, J. E.. 2021-12-14. An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome. https://doi.org/10.1101/2021.12.13.472243

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