Mycn facilitates hematopoietic stem and progenitor cell generation from endothelial cells by inhibiting adhesion signaling.

Abstract

Hematopoietic stem and progenitor cells (HSPCs) arise from hemogenic endothelial cells (HECs) via the endothelial-to-hematopoietic transition (EHT). As a signature gene of hematopoietic stem cell-primed HECs, Mycn is highly expressed in these cells alongside its paralog, Myc. However, their roles and underlying mechanisms in EHT remain unclear. Here, we demonstrate that endothelial-specific deletion of Mycn, but not Myc, impairs HSPC formation in mouse embryos. Single-cell transcriptomics and functional assays reveal that Mycn deficiency specifically attenuates the HEC-to-HSPC transition but not thereafter. We also establish a mosaic analysis strategy to distinguish Mycn deletion states in mutant embryos, enabling precise characterization. Unlike control HECs that downregulate adhesion signatures during their specification, Mycn-deficient HECs aberrantly upregulate adhesion pathways. Inhibiting focal adhesion kinase, a critical modulator of cell adhesion, rescues HSPC production in Mycn-deficient explant cultures. These findings uncover a regulatory mechanism whereby Mycn promotes HSPC generation from endothelial cells by suppressing adhesion signaling.