Kainate receptors coordinate primitive hematopoiesis and hemogenic niche organization to promote hematopoietic stem cell development
- 1Department of Cell Biology, Van Andel Institute, Grand Rapids, MI, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts,
Abstract
The adult hematopoietic system is established during embryogenesis through the generation of hematopoietic stem and progenitor cells (HSPCs) within specialized transient niches, yet the signaling mechanisms that coordinate this process remain poorly understood. Here, we identify a developmental role for kainate receptors (KARs), glutamate-gated ion channels classically associated with excitatory neurotransmission, in coordinating primitive hematopoiesis and hemogenic niche formation in zebrafish. Loss of the KAR subunits encoded by grik1b or grik5 depletes primitive blood cells and disrupts hemogenic niche organization. These defects are accompanied by endothelial oxidative stress and impaired Notch signaling, which together reduce HSPC emergence and limit the clonal diversity of the adult hematopoietic stem cell pool. Shifting primitive hematopoietic output away from erythropoiesis and toward myelopoiesis restored macrophage niche colonization, endothelial Notch activity, and HSPC formation in KAR-deficient embryos. Moreover, hemogenic cell-specific Notch reactivation rescued HSPC production, demonstrating that KAR-dependent primitive hematopoiesis regulates this process through endothelial Notch signaling. Lastly, conserved KAR expression in endothelial and hematopoietic populations across zebrafish, mouse, and human suggests that these receptors may regulate blood development across multiple cellular components. Together, these findings reveal that glutamate receptor signaling extends beyond its well-established functions in neuronal transmission to coordinate the developmental processes that establish the blood system.
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BibTeX
@misc{paradakusz2026kainate,
title = {{Kainate receptors coordinate primitive hematopoiesis and hemogenic niche organization to promote hematopoietic stem cell development}},
author = {M. Parada-Kusz and S. J. Wattrus and J. Jacobs and A. D. Ide and J. Y. Shigeta and V. di Natale and M. T. Elaswad and Z. Fu and E. R. Goering and S. Blackwood and T. Walton and A. E. Clatworthy and S. Grainger and D. T. Hung},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753284},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753284v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Kainate receptors coordinate primitive hematopoiesis and hemogenic niche organization to promote hematopoietic stem cell development
AU - M. Parada-Kusz
AU - S. J. Wattrus
AU - J. Jacobs
AU - A. D. Ide
AU - J. Y. Shigeta
AU - V. di Natale
AU - M. T. Elaswad
AU - Z. Fu
AU - E. R. Goering
AU - S. Blackwood
AU - T. Walton
AU - A. E. Clatworthy
AU - S. Grainger
AU - D. T. Hung
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753284
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753284v1
AB - The adult hematopoietic system is established during embryogenesis through the generation of hematopoietic stem and progenitor cells (HSPCs) within specialized transient niches, yet the signaling mechanisms that coordinate this process remain poorly understood. Here, we identify a developmental role for kainate receptors (KARs), glutamate-gated ion channels classically associated with excitatory neurotransmission, in coordinating primitive hematopoiesis and hemogenic niche formation in zebrafish. Loss of the KAR subunits encoded by grik1b or grik5 depletes primitive blood cells and disrupts hemogenic niche organization. These defects are accompanied by endothelial oxidative stress and impaired Notch signaling, which together reduce HSPC emergence and limit the clonal diversity of the adult hematopoietic stem cell pool. Shifting primitive hematopoietic output away from erythropoiesis and toward myelopoiesis restored macrophage niche colonization, endothelial Notch activity, and HSPC formation in KAR-deficient embryos. Moreover, hemogenic cell-specific Notch reactivation rescued HSPC production, demonstrating that KAR-dependent primitive hematopoiesis regulates this process through endothelial Notch signaling. Lastly, conserved KAR expression in endothelial and hematopoietic populations across zebrafish, mouse, and human suggests that these receptors may regulate blood development across multiple cellular components. Together, these findings reveal that glutamate receptor signaling extends beyond its well-established functions in neuronal transmission to coordinate the developmental processes that establish the blood system.
ER -