Cul4a promotes zebrafish primitive erythropoiesis via upregulating scl and gata1 expression.

CUL4A and CUL4B are closely related members in Cullin family and can each assemble a Cullin-RING E3 ligase complex (Cullin-RING Ligase 4A or 4B, CRL4A, or CRL4B) and participate in a variety of biological processes. Previously we showed that zebrafish cul4a, but not cul4b, is essential for cardiac and pectoral fin development. Here, we have identified cul4a as a crucial regulator of primitive erythropoiesis in zebrafish embryonic development. Depletion of cul4a resulted in a striking reduction of erythroid cells due to the inhibition of erythroid differentiation. Transcript levels for early hematopoietic regulatory genes including scl, lmo2, and gata1 are significantly reduced in cul4a-deficient embryos. Mechanistically, we demonstrated that scl and gata1, the central regulators of primitive hematopoiesis for erythroid determination, are transcriptionally upregulated by cul4a. These findings demonstrate an important role for cul4a in primitive erythropoiesis and may bear implications in regeneration medicine of anemia and related diseases.