p65 signaling dynamics drive the developmental progression of hematopoietic stem and progenitor cells through cell cycle regulation.
Animals
Zebrafish
/ embryology
Hematopoietic Stem Cells
/ metabolism
Signal Transduction
Humans
Cell Cycle
Zebrafish Proteins
/ metabolism
Embryo, Nonmammalian
/ metabolism
Transcription Factor RelA
/ metabolism
Gene Expression Regulation, Developmental
Hematopoiesis
Cell Differentiation
Cell Proliferation
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 Sep 2024
06 Sep 2024
Historique:
received:
18
01
2024
accepted:
20
08
2024
medline:
7
9
2024
pubmed:
7
9
2024
entrez:
6
9
2024
Statut:
epublish
Résumé
Most gene functions have been discovered through phenotypic observations under loss of function experiments that lack temporal control. However, cell signaling relies on limited transcriptional effectors, having to be re-used temporally and spatially within the organism. Despite that, the dynamic nature of signaling pathways have been overlooked due to the difficulty on their assessment, resulting in important bottlenecks. Here, we have utilized the rapid and synchronized developmental transitions occurring within the zebrafish embryo, in conjunction with custom NF-kB reporter embryos driving destabilized fluorophores that report signaling dynamics in real time. We reveal that NF-kB signaling works as a clock that controls the developmental progression of hematopoietic stem and progenitor cells (HSPCs) by two p65 activity waves that inhibit cell cycle. Temporal disruption of each wave results in contrasting phenotypic outcomes: loss of HSPCs due to impaired specification versus proliferative expansion and failure to delaminate from their niche. We also show functional conservation during human hematopoietic development using iPSC models. Our work identifies p65 as a previously unrecognized contributor to cell cycle regulation, revealing why and when pro-inflammatory signaling is required during HSPC development. It highlights the importance of considering and leveraging cell signaling as a temporally dynamic entity.
Identifiants
pubmed: 39242546
doi: 10.1038/s41467-024-51922-5
pii: 10.1038/s41467-024-51922-5
doi:
Substances chimiques
Zebrafish Proteins
0
Transcription Factor RelA
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
7787Informations de copyright
© 2024. The Author(s).
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