Cargando…
Dbx2, an Aging-Related Homeobox Gene, Inhibits the Proliferation of Adult Neural Progenitors
In the adult mouse brain, the subventricular zone (SVZ) underlying the lateral ventricles harbours a population of quiescent neural stem cells, which can be activated (aNSCs) to initiate proliferation and generate a neurogenic lineage consisting of transit amplifying progenitors (TAPs), neuroblasts...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661760/ https://www.ncbi.nlm.nih.gov/pubmed/37605090 http://dx.doi.org/10.1007/s12015-023-10600-7 |
_version_ | 1785138047814205440 |
---|---|
author | Giuliani, Andrea Licursi, Valerio Nisi, Paola S. Fiore, Mario D’Angelo, Sara Biagioni, Stefano Negri, Rodolfo Rugg-Gunn, Peter J. Cacci, Emanuele Lupo, Giuseppe |
author_facet | Giuliani, Andrea Licursi, Valerio Nisi, Paola S. Fiore, Mario D’Angelo, Sara Biagioni, Stefano Negri, Rodolfo Rugg-Gunn, Peter J. Cacci, Emanuele Lupo, Giuseppe |
author_sort | Giuliani, Andrea |
collection | PubMed |
description | In the adult mouse brain, the subventricular zone (SVZ) underlying the lateral ventricles harbours a population of quiescent neural stem cells, which can be activated (aNSCs) to initiate proliferation and generate a neurogenic lineage consisting of transit amplifying progenitors (TAPs), neuroblasts (NBs) and newborn neurons. This process is markedly reduced during aging. Recent studies suggest that the aged SVZ niche decreases the pool of proliferating neural/stem progenitor cells (NSPCs), and hence adult neurogenesis, by causing transcriptomic changes that promote NSC quiescence. The transcription factors that mediate these changes, however, remain unclear. We previously found that the homeobox gene Dbx2 is upregulated in NSPCs of the aged mouse SVZ and can inhibit the growth of NSPC cultures. Here, we further investigate its role as a candidate transcriptional regulator of neurogenic decline. We show that Dbx2 expression is downregulated by Epidermal Growth Factor receptor signaling, which promotes NSPC proliferation and decreases in the aged SVZ. By means of transgenic NSPC lines overexpressing Dbx2, we also show that this gene inhibits NSPC proliferation by hindering the G2/M transition. Furthermore, we exploit RNA sequencing of transgenic NSPCs to elucidate the transcriptomic networks modulated by Dbx2. Among the top hits, we report the downregulation of the molecular pathways implicated in cell cycle progression. Accordingly, we find that Dbx2 function is negatively correlated with the transcriptional signatures of proliferative NSPCs (aNSCs, TAPs and early NBs). These results point to Dbx2 as a transcription factor relaying the anti-neurogenic input of the aged niche to the NSPC transcriptome. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12015-023-10600-7. |
format | Online Article Text |
id | pubmed-10661760 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-106617602023-08-22 Dbx2, an Aging-Related Homeobox Gene, Inhibits the Proliferation of Adult Neural Progenitors Giuliani, Andrea Licursi, Valerio Nisi, Paola S. Fiore, Mario D’Angelo, Sara Biagioni, Stefano Negri, Rodolfo Rugg-Gunn, Peter J. Cacci, Emanuele Lupo, Giuseppe Stem Cell Rev Rep Article In the adult mouse brain, the subventricular zone (SVZ) underlying the lateral ventricles harbours a population of quiescent neural stem cells, which can be activated (aNSCs) to initiate proliferation and generate a neurogenic lineage consisting of transit amplifying progenitors (TAPs), neuroblasts (NBs) and newborn neurons. This process is markedly reduced during aging. Recent studies suggest that the aged SVZ niche decreases the pool of proliferating neural/stem progenitor cells (NSPCs), and hence adult neurogenesis, by causing transcriptomic changes that promote NSC quiescence. The transcription factors that mediate these changes, however, remain unclear. We previously found that the homeobox gene Dbx2 is upregulated in NSPCs of the aged mouse SVZ and can inhibit the growth of NSPC cultures. Here, we further investigate its role as a candidate transcriptional regulator of neurogenic decline. We show that Dbx2 expression is downregulated by Epidermal Growth Factor receptor signaling, which promotes NSPC proliferation and decreases in the aged SVZ. By means of transgenic NSPC lines overexpressing Dbx2, we also show that this gene inhibits NSPC proliferation by hindering the G2/M transition. Furthermore, we exploit RNA sequencing of transgenic NSPCs to elucidate the transcriptomic networks modulated by Dbx2. Among the top hits, we report the downregulation of the molecular pathways implicated in cell cycle progression. Accordingly, we find that Dbx2 function is negatively correlated with the transcriptional signatures of proliferative NSPCs (aNSCs, TAPs and early NBs). These results point to Dbx2 as a transcription factor relaying the anti-neurogenic input of the aged niche to the NSPC transcriptome. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12015-023-10600-7. Springer US 2023-08-22 2023 /pmc/articles/PMC10661760/ /pubmed/37605090 http://dx.doi.org/10.1007/s12015-023-10600-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Giuliani, Andrea Licursi, Valerio Nisi, Paola S. Fiore, Mario D’Angelo, Sara Biagioni, Stefano Negri, Rodolfo Rugg-Gunn, Peter J. Cacci, Emanuele Lupo, Giuseppe Dbx2, an Aging-Related Homeobox Gene, Inhibits the Proliferation of Adult Neural Progenitors |
title | Dbx2, an Aging-Related Homeobox Gene, Inhibits the Proliferation of Adult Neural Progenitors |
title_full | Dbx2, an Aging-Related Homeobox Gene, Inhibits the Proliferation of Adult Neural Progenitors |
title_fullStr | Dbx2, an Aging-Related Homeobox Gene, Inhibits the Proliferation of Adult Neural Progenitors |
title_full_unstemmed | Dbx2, an Aging-Related Homeobox Gene, Inhibits the Proliferation of Adult Neural Progenitors |
title_short | Dbx2, an Aging-Related Homeobox Gene, Inhibits the Proliferation of Adult Neural Progenitors |
title_sort | dbx2, an aging-related homeobox gene, inhibits the proliferation of adult neural progenitors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661760/ https://www.ncbi.nlm.nih.gov/pubmed/37605090 http://dx.doi.org/10.1007/s12015-023-10600-7 |
work_keys_str_mv | AT giulianiandrea dbx2anagingrelatedhomeoboxgeneinhibitstheproliferationofadultneuralprogenitors AT licursivalerio dbx2anagingrelatedhomeoboxgeneinhibitstheproliferationofadultneuralprogenitors AT nisipaolas dbx2anagingrelatedhomeoboxgeneinhibitstheproliferationofadultneuralprogenitors AT fioremario dbx2anagingrelatedhomeoboxgeneinhibitstheproliferationofadultneuralprogenitors AT dangelosara dbx2anagingrelatedhomeoboxgeneinhibitstheproliferationofadultneuralprogenitors AT biagionistefano dbx2anagingrelatedhomeoboxgeneinhibitstheproliferationofadultneuralprogenitors AT negrirodolfo dbx2anagingrelatedhomeoboxgeneinhibitstheproliferationofadultneuralprogenitors AT rugggunnpeterj dbx2anagingrelatedhomeoboxgeneinhibitstheproliferationofadultneuralprogenitors AT cacciemanuele dbx2anagingrelatedhomeoboxgeneinhibitstheproliferationofadultneuralprogenitors AT lupogiuseppe dbx2anagingrelatedhomeoboxgeneinhibitstheproliferationofadultneuralprogenitors |