Haematopoietic stem and progenitor cells (HSPCs) arise from the aorta-gonad-mesonephros and migrate to the caudal haematopoietic tissue (CHT) in zebrafish, where nascent HSPCs undergo tightly controlled proliferation and differentiation to promote definitive haematopoiesis. Effective expansion of HSPCs requires the coordination of well-established vesicle trafficking systems and appropriate transcription factors. However, the underlying molecules are yet to be identified. Using large-scale genetic screening of zebrafish larvae, Tango6 of the coat protein complex I (COPI) vesicle trafficking system was found to be indispensable for HSPC proliferation and definitive haematopoiesis. Homozygous tango6cq72 mutants display defective expansion of HSPCs in the CHT and compromised haematopoiesis. However, haematopoietic overexpression of Tango6 promoted haematopoietic expansion. tango6 deficiency caused a decline in RNA polymerase II subunit B and accumulation of DNA damage, which suppressed cell expansion in a P53-dependent manner. ikzf1 and cmyb (myb), two indispensable haematopoietic transcription factors, are targets of P53 and are used by tango6 in haematopoiesis. The haematopoietic phenotype was partially recovered by compensating for loss of ikzf1 and cmyb in tango6cq72 mutants. This study reveals a vesicle trafficking-mediated Tango6-P53-Ikzf1/Cmyb axis in zebrafish definitive haematopoiesis.

Keywords:
Definitive haematopoiesis, Tango6, Rpb2, P53, Ikzf1, Cmyb, Zebrafish

Author contributions

Conceptualization: S.L., Z.F., L. Li; Methodology: Z.F., M.S., C.L., L. Luo, X.T.; Software: X.T.; Validation: Y.X., H.C.; Investigation: S.L., M.S., C.L., X.T., L. Li; Resources: L. Luo, X.T.; Data curation: S.L., Z.F., Y.X., H.C., F.Z.; Writing - original draft: S.L.; Writing - review & editing: X.T., L. Li; Visualization: Z.F., F.Z.; Supervision: L. Li; Project administration: S.L., Z.F., L. Li; Funding acquisition: X.T., L. Li.

Funding

This work was supported by the National Key Research and Development Program of China (2023YFA1800100), by the National Natural Science Foundation of China (32270873 and 31822033), and by the Chongqing Population and Health Special Funding of China (CSTB2023TIAD-KPX0056).

Data availability

The RNA-seq data have been deposited in the Sequence Read Archive under accession number PRJNA1145276.

© 2025. Published by The Company of Biologists
2025
https://www.biologists.com/user-licence-1-1/
You do not currently have access to this content.