Tango6 regulates HSPC proliferation and definitive haematopoiesis via Ikzf1 and Cmyb in caudal haematopoietic tissue

ABSTRACT 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.