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RGC-32 Acts as a Hub to Regulate the Transcriptomic Changes Associated With Astrocyte Development and Reactive Astrocytosis

Response Gene to Complement 32 (RGC-32) is an important mediator of the TGF-β signaling pathway, and an increasing amount of evidence implicates this protein in regulating astrocyte biology. We showed recently that spinal cord astrocytes in mice lacking RGC-32 display an immature phenotype reminisce...

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Autores principales: Tatomir, Alexandru, Beltrand, Austin, Nguyen, Vinh, Courneya, Jean-Paul, Boodhoo, Dallas, Cudrici, Cornelia, Muresanu, Dafin F., Rus, Violeta, Badea, Tudor C., Rus, Horea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358671/
https://www.ncbi.nlm.nih.gov/pubmed/34394104
http://dx.doi.org/10.3389/fimmu.2021.705308
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author Tatomir, Alexandru
Beltrand, Austin
Nguyen, Vinh
Courneya, Jean-Paul
Boodhoo, Dallas
Cudrici, Cornelia
Muresanu, Dafin F.
Rus, Violeta
Badea, Tudor C.
Rus, Horea
author_facet Tatomir, Alexandru
Beltrand, Austin
Nguyen, Vinh
Courneya, Jean-Paul
Boodhoo, Dallas
Cudrici, Cornelia
Muresanu, Dafin F.
Rus, Violeta
Badea, Tudor C.
Rus, Horea
author_sort Tatomir, Alexandru
collection PubMed
description Response Gene to Complement 32 (RGC-32) is an important mediator of the TGF-β signaling pathway, and an increasing amount of evidence implicates this protein in regulating astrocyte biology. We showed recently that spinal cord astrocytes in mice lacking RGC-32 display an immature phenotype reminiscent of progenitors and radial glia, with an overall elongated morphology, increased proliferative capacity, and increased expression of progenitor markers when compared to their wild-type (WT) counterparts that make them incapable of undergoing reactive changes during the acute phase of experimental autoimmune encephalomyelitis (EAE). Here, in order to decipher the molecular networks underlying RGC-32’s ability to regulate astrocytic maturation and reactivity, we performed next-generation sequencing of RNA from WT and RGC-32 knockout (KO) neonatal mouse brain astrocytes, either unstimulated or stimulated with the pleiotropic cytokine TGF-β. Pathway enrichment analysis showed that RGC-32 is critical for the TGF-β-induced up-regulation of transcripts encoding proteins involved in brain development and tissue remodeling, such as axonal guidance molecules, transcription factors, extracellular matrix (ECM)-related proteins, and proteoglycans. Our next-generation sequencing of RNA analysis also demonstrated that a lack of RGC-32 results in a significant induction of WD repeat and FYVE domain-containing protein 1 (Wdfy1) and stanniocalcin-1 (Stc1). Immunohistochemical analysis of spinal cords isolated from normal adult mice and mice with EAE at the peak of disease showed that RGC-32 is necessary for the in vivo expression of ephrin receptor type A7 in reactive astrocytes, and that the lack of RGC-32 results in a higher number of homeodomain-only protein homeobox (HOPX)(+) and CD133(+) radial glia cells. Collectively, these findings suggest that RGC-32 plays a major role in modulating the transcriptomic changes in astrocytes that ultimately lead to molecular programs involved in astrocytic differentiation and reactive changes during neuroinflammation.
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spelling pubmed-83586712021-08-13 RGC-32 Acts as a Hub to Regulate the Transcriptomic Changes Associated With Astrocyte Development and Reactive Astrocytosis Tatomir, Alexandru Beltrand, Austin Nguyen, Vinh Courneya, Jean-Paul Boodhoo, Dallas Cudrici, Cornelia Muresanu, Dafin F. Rus, Violeta Badea, Tudor C. Rus, Horea Front Immunol Immunology Response Gene to Complement 32 (RGC-32) is an important mediator of the TGF-β signaling pathway, and an increasing amount of evidence implicates this protein in regulating astrocyte biology. We showed recently that spinal cord astrocytes in mice lacking RGC-32 display an immature phenotype reminiscent of progenitors and radial glia, with an overall elongated morphology, increased proliferative capacity, and increased expression of progenitor markers when compared to their wild-type (WT) counterparts that make them incapable of undergoing reactive changes during the acute phase of experimental autoimmune encephalomyelitis (EAE). Here, in order to decipher the molecular networks underlying RGC-32’s ability to regulate astrocytic maturation and reactivity, we performed next-generation sequencing of RNA from WT and RGC-32 knockout (KO) neonatal mouse brain astrocytes, either unstimulated or stimulated with the pleiotropic cytokine TGF-β. Pathway enrichment analysis showed that RGC-32 is critical for the TGF-β-induced up-regulation of transcripts encoding proteins involved in brain development and tissue remodeling, such as axonal guidance molecules, transcription factors, extracellular matrix (ECM)-related proteins, and proteoglycans. Our next-generation sequencing of RNA analysis also demonstrated that a lack of RGC-32 results in a significant induction of WD repeat and FYVE domain-containing protein 1 (Wdfy1) and stanniocalcin-1 (Stc1). Immunohistochemical analysis of spinal cords isolated from normal adult mice and mice with EAE at the peak of disease showed that RGC-32 is necessary for the in vivo expression of ephrin receptor type A7 in reactive astrocytes, and that the lack of RGC-32 results in a higher number of homeodomain-only protein homeobox (HOPX)(+) and CD133(+) radial glia cells. Collectively, these findings suggest that RGC-32 plays a major role in modulating the transcriptomic changes in astrocytes that ultimately lead to molecular programs involved in astrocytic differentiation and reactive changes during neuroinflammation. Frontiers Media S.A. 2021-07-29 /pmc/articles/PMC8358671/ /pubmed/34394104 http://dx.doi.org/10.3389/fimmu.2021.705308 Text en Copyright © 2021 Tatomir, Beltrand, Nguyen, Courneya, Boodhoo, Cudrici, Muresanu, Rus, Badea and Rus https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Tatomir, Alexandru
Beltrand, Austin
Nguyen, Vinh
Courneya, Jean-Paul
Boodhoo, Dallas
Cudrici, Cornelia
Muresanu, Dafin F.
Rus, Violeta
Badea, Tudor C.
Rus, Horea
RGC-32 Acts as a Hub to Regulate the Transcriptomic Changes Associated With Astrocyte Development and Reactive Astrocytosis
title RGC-32 Acts as a Hub to Regulate the Transcriptomic Changes Associated With Astrocyte Development and Reactive Astrocytosis
title_full RGC-32 Acts as a Hub to Regulate the Transcriptomic Changes Associated With Astrocyte Development and Reactive Astrocytosis
title_fullStr RGC-32 Acts as a Hub to Regulate the Transcriptomic Changes Associated With Astrocyte Development and Reactive Astrocytosis
title_full_unstemmed RGC-32 Acts as a Hub to Regulate the Transcriptomic Changes Associated With Astrocyte Development and Reactive Astrocytosis
title_short RGC-32 Acts as a Hub to Regulate the Transcriptomic Changes Associated With Astrocyte Development and Reactive Astrocytosis
title_sort rgc-32 acts as a hub to regulate the transcriptomic changes associated with astrocyte development and reactive astrocytosis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358671/
https://www.ncbi.nlm.nih.gov/pubmed/34394104
http://dx.doi.org/10.3389/fimmu.2021.705308
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