A zebrafish model for HAX1-associated congenital neutropenia

Severe congenital neutropenia is a rare heterogeneous group of diseases, characterized by an arrest of granulocyte maturation. Autosomal recessive mutations in the HAX1 gene are frequently detected in affected individuals. However, the precise role of HAX1 during neutrophil differentiation is poorly understood. To date, no reliable animal model has been established to study HAX1-associated congenital neutropenia. Here we show that knockdown of zebrafish hax1 impairs neutrophil development without affecting other myeloid cells and erythrocytes. Furthermore, we found that interference with Hax1 function decreases the expression level of key target genes of the granulocyte colony-stimulating factor signaling pathway. The reduced neutrophil numbers in the morphants could be reversed by granulocyte colony-stimulating factor, which is also the main therapeutic intervention for patients who have congenital neutropenia. Our results demonstrate that the zebrafish is a suitable model for HAX1-associated neutropenia. We anticipate that this model will serve as an in vivo platform to identify new avenues for developing tailored therapeutic strategies for patients with congenital neutropenia, particularly for those individuals who do not respond to granulocyte colony-stimulating factor treatment.