Cargando…
Single nuclei RNA sequencing of the rat AP and NTS following GDF15 treatment
OBJECTIVE: Growth differentiation factor 15 (GDF15) is known to play a role in feeding, nausea, and body weight, with action through the GFRAL-RET receptor complex in the area postrema (AP) and nucleus tractus solitarius (NTS). To further elucidate the underlying cell type-specific molecular mechani...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749158/ https://www.ncbi.nlm.nih.gov/pubmed/34942400 http://dx.doi.org/10.1016/j.molmet.2021.101422 |
_version_ | 1784631168023396352 |
---|---|
author | Reiner, Benjamin C. Crist, Richard C. Borner, Tito Doyle, Robert P. Hayes, Matthew R. De Jonghe, Bart C. |
author_facet | Reiner, Benjamin C. Crist, Richard C. Borner, Tito Doyle, Robert P. Hayes, Matthew R. De Jonghe, Bart C. |
author_sort | Reiner, Benjamin C. |
collection | PubMed |
description | OBJECTIVE: Growth differentiation factor 15 (GDF15) is known to play a role in feeding, nausea, and body weight, with action through the GFRAL-RET receptor complex in the area postrema (AP) and nucleus tractus solitarius (NTS). To further elucidate the underlying cell type-specific molecular mechanisms downstream of GDF15 signaling, we used a single nuclei RNA sequencing (snRNAseq) approach to profile AP and NTS cellular subtype-specific transcriptomes after systemic GDF15 treatment. METHODS: AP and NTS micropunches were used for snRNAseq from Sprague Dawley rats 6 h following GDF15 or saline injection, and Seurat was used to identify cellular subtypes and cell type-specific alterations in gene expression that were due to the direct and secondary effects of systemic GDF15 treatment. RESULTS: Using the transcriptome profile of ∼35,000 individual AP/NTS nuclei, we identified 19 transcriptomically distinct cellular subtypes, including a single population Gfral and Ret positive excitatory neurons, representing the primary site of action for GDF15. A total of ∼600 cell type-specific differential expression events were identified in neurons and glia, including the identification of transcriptome alterations specific to the direct effects of GDF15 in the Gfral-Ret positive excitatory neurons and shared transcriptome alterations across neuronal and glial cell types. Downstream analyses identified shared and cell type-specific alterations in signaling pathways and upstream regulatory mechanisms of the observed transcriptome alterations. CONCLUSIONS: These data provide a considerable advance in our understanding of AP and NTS cell type-specific molecular mechanisms associated with GDF15 signaling. The identified cellular subtype-specific regulatory mechanism and signaling pathways likely represent important targets for future pharmacotherapies. |
format | Online Article Text |
id | pubmed-8749158 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-87491582022-01-13 Single nuclei RNA sequencing of the rat AP and NTS following GDF15 treatment Reiner, Benjamin C. Crist, Richard C. Borner, Tito Doyle, Robert P. Hayes, Matthew R. De Jonghe, Bart C. Mol Metab Brief Communication OBJECTIVE: Growth differentiation factor 15 (GDF15) is known to play a role in feeding, nausea, and body weight, with action through the GFRAL-RET receptor complex in the area postrema (AP) and nucleus tractus solitarius (NTS). To further elucidate the underlying cell type-specific molecular mechanisms downstream of GDF15 signaling, we used a single nuclei RNA sequencing (snRNAseq) approach to profile AP and NTS cellular subtype-specific transcriptomes after systemic GDF15 treatment. METHODS: AP and NTS micropunches were used for snRNAseq from Sprague Dawley rats 6 h following GDF15 or saline injection, and Seurat was used to identify cellular subtypes and cell type-specific alterations in gene expression that were due to the direct and secondary effects of systemic GDF15 treatment. RESULTS: Using the transcriptome profile of ∼35,000 individual AP/NTS nuclei, we identified 19 transcriptomically distinct cellular subtypes, including a single population Gfral and Ret positive excitatory neurons, representing the primary site of action for GDF15. A total of ∼600 cell type-specific differential expression events were identified in neurons and glia, including the identification of transcriptome alterations specific to the direct effects of GDF15 in the Gfral-Ret positive excitatory neurons and shared transcriptome alterations across neuronal and glial cell types. Downstream analyses identified shared and cell type-specific alterations in signaling pathways and upstream regulatory mechanisms of the observed transcriptome alterations. CONCLUSIONS: These data provide a considerable advance in our understanding of AP and NTS cell type-specific molecular mechanisms associated with GDF15 signaling. The identified cellular subtype-specific regulatory mechanism and signaling pathways likely represent important targets for future pharmacotherapies. Elsevier 2021-12-21 /pmc/articles/PMC8749158/ /pubmed/34942400 http://dx.doi.org/10.1016/j.molmet.2021.101422 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Brief Communication Reiner, Benjamin C. Crist, Richard C. Borner, Tito Doyle, Robert P. Hayes, Matthew R. De Jonghe, Bart C. Single nuclei RNA sequencing of the rat AP and NTS following GDF15 treatment |
title | Single nuclei RNA sequencing of the rat AP and NTS following GDF15 treatment |
title_full | Single nuclei RNA sequencing of the rat AP and NTS following GDF15 treatment |
title_fullStr | Single nuclei RNA sequencing of the rat AP and NTS following GDF15 treatment |
title_full_unstemmed | Single nuclei RNA sequencing of the rat AP and NTS following GDF15 treatment |
title_short | Single nuclei RNA sequencing of the rat AP and NTS following GDF15 treatment |
title_sort | single nuclei rna sequencing of the rat ap and nts following gdf15 treatment |
topic | Brief Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749158/ https://www.ncbi.nlm.nih.gov/pubmed/34942400 http://dx.doi.org/10.1016/j.molmet.2021.101422 |
work_keys_str_mv | AT reinerbenjaminc singlenucleirnasequencingoftheratapandntsfollowinggdf15treatment AT cristrichardc singlenucleirnasequencingoftheratapandntsfollowinggdf15treatment AT bornertito singlenucleirnasequencingoftheratapandntsfollowinggdf15treatment AT doylerobertp singlenucleirnasequencingoftheratapandntsfollowinggdf15treatment AT hayesmatthewr singlenucleirnasequencingoftheratapandntsfollowinggdf15treatment AT dejonghebartc singlenucleirnasequencingoftheratapandntsfollowinggdf15treatment |