PUBLICATION
p65 signaling dynamics drive the developmental progression of hematopoietic stem and progenitor cells through cell cycle regulation
- Authors
- Campbell, C.A., Calderon, R., Pavani, G., Cheng, X., Barakat, R., Snella, E., Liu, F., Peng, X., Essner, J.J., Dorman, K.S., McGrail, M., Gadue, P., French, D.L., Espin-Palazon, R.
- ID
- ZDB-PUB-240908-9
- Date
- 2024
- Source
- Nature communications 15: 77877787 (Journal)
- Registered Authors
- Campbell, Clyde, Espín-Palazón, Raquel, Essner, Jeffrey, McGrail, Maura, Snella, Elizabeth
- Keywords
- none
- Datasets
- GEO:GSE253758
- MeSH Terms
-
- Animals
- Cell Cycle*
- Cell Differentiation
- Cell Proliferation
- Embryo, Nonmammalian/metabolism
- Gene Expression Regulation, Developmental
- Hematopoiesis
- Hematopoietic Stem Cells*/cytology
- Hematopoietic Stem Cells*/metabolism
- Humans
- Signal Transduction*
- Transcription Factor RelA/metabolism
- Zebrafish*/embryology
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 39242546 Full text @ Nat. Commun.
Citation
Campbell, C.A., Calderon, R., Pavani, G., Cheng, X., Barakat, R., Snella, E., Liu, F., Peng, X., Essner, J.J., Dorman, K.S., McGrail, M., Gadue, P., French, D.L., Espin-Palazon, R. (2024) p65 signaling dynamics drive the developmental progression of hematopoietic stem and progenitor cells through cell cycle regulation. Nature communications. 15:77877787.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping