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

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.