Kainate receptors couple primitive hematopoiesis to Notch-dependent HSPC emergence by shaping hemogenic niche cellular architecture

ABSTRACT: The establishment of lifelong hematopoiesis depends on a transient, instructive embryonic niche that enables hematopoietic stem and progenitor cell (HSPC) emergence from hemogenic endothelium. We identify a requirement for kainate receptors (KARs), a class of glutamate-gated ion channels, in primitive hematopoiesis and hemogenic niche organization, which together support Notch-dependent HSPC emergence. KAR disruption or inhibition causes progressive primitive blood cell loss and niche disorganization, with erythrocyte retention, reduced macrophage colonization, and impaired HSPC output. Transcriptomic profiling of endothelial cells prior to HSPC emergence reveals that loss of KAR subunits encoded by grik1b or grik5 triggers oxidative stress and apoptotic programs, while dysregulating Notch-responsive genes and suppressing proliferative signatures. Biasing primitive hematopoiesis toward myelopoiesis restores macrophage niche colonization, Notch activity in hemogenic endothelium, and HSPC emergence in KAR-deficient embryos, while hemogenic cell-specific Notch reactivation rescues HSPC output, placing reduced hemogenic endothelial Notch activity downstream of the primitive hematopoietic defect. Conserved expression of KAR subunit orthologs across mouse and human mesodermal, endothelial, and hematopoietic compartments supports a potential role for KAR signaling in mammalian blood development. Finally, cellular barcoding reveals that transient embryonic KAR knockdown reduces the diversity of hematopoietic stem cell clones contributing to adult blood production. These findings identify KAR signaling as a regulator of the hemogenic niche architecture linking primitive hematopoiesis to HSPC emergence, offering new insight into how ion channel signaling shapes hematopoietic stem cell ontogeny.

ORGANISM(S): Danio rerio

PROVIDER: GSE342053 | GEO | 2026/09/22

REPOSITORIES: GEO