Dataset Information

Ninjurins 1 Regulate Hematopoietic Stem Cell Amplification Through Canonical WNT Signaling Independently of Plasma Membrane Rupture Activity

ABSTRACT: Ninjurin-1 (NINJ1), a protein recently linked to plasma membrane rupture (PMR) during inflammasome activation, plays a well-established role in cell death. However, its function in hematopoiesis has remained unexplored. In this study, we identify a novel, PMR-independent role for Ninj1 in regulating hematopoiesis using zebrafish models. Ninj1 deficiency resulted in significantly reduced neutrophil, erythrocyte, and hematopoietic stem/progenitor cell (HSPC) numbers, independently of its plasma membrane rupture (PMR) activity. Surprisingly, Ninj1 deficiency also alleviated neutrophilia and keratinocyte hyperproliferation in a chronic inflammation model, revealing a role beyond inflammasome-mediated cell death. To further investigate thisnoncanonical function, we identified PMR-deficient Ninj1 mutants (A56P and D50A). Expression of the A56P mutant rescued hematopoietic defects in Ninj1-deficient larvae, while the dominant-negative D50A mutant recapitulated the phenotypes of Ninj1 deficiency, confirming that Ninj1 regulates hematopoiesis independently of PMR. Furthermore, Ninj1 deficiency increased susceptibility to intracellular bacterial infection due to impaired neutrophil and macrophage recruitment, while overexpression of the A56P mutant enhanced immune cell recruitment and resistance to infection. Finally, we discovered that Ninj1 and Ninj2 cooperatively regulate the amplification of nascent hematopoietic stem cells (HSCs) from the hemogenic endothelium via canonical Wnt signaling. Importantly, this regulatory mechanism is conserved in human HSPCs, underscoring its evolutionary significance and translational potential. These findings position Ninjurins as critical regulators of HSC development and immune responses, with promising implications for enhancing HSC production in regenerative medicine and developing therapies for hematological and infectious diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE330969 | GEO | 2026/07/02

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:We are studying the natural history, pathogenesis and treatment of patients with WHIM syndrome, an immunodeficiency disorder characterized by warts, hypogammaglobulinemia, recurrent infections and neutropenia usually due to autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. We have identified a patient born with WHIM syndrome and the WHIM mutation CXCR4R334X who has been disease-free for 20 years and who lacks CXCR4R334X in myeloid cells, the cells that drive disease manifestations. She is a genetic and hematopoietic mosaic, since she still has the mutation in lymphoid cells and non-hematopoietic cells. Cytogenetics and microarray analysis revealed that the mechanism of loss of the mutation was deletion of the mutant allele from one copy of chromosome 2. Whole genome sequencing of patient neutrophil and skin fibroblast genomic DNA revealed that the mechanism of deletion was chromothripsis, a process of chromosome shattering resulting in deletions and rearrangements of the non-deleted chromosomal segments. In the patient, this process evidently occurred in a single hematopoietic stem cell (HSC), resulting in deletion of the disease allele CXCR4R334X and one copy of 163 other genes on chromosome 2. This HSC evidently acquired a growth advantage and repopulated the HSC population and the myeloid lineage. Consistent with this, studies using gene targeted mice in competitive bone marrow transplantation experiments revealed that selective Cxcr4 haploinsufficiency (inactivation of one copy of Cxcr4 and not of any other genes) was sufficient to confer a strong engraftment advantage over bone marrow cells from wild type mice as well as bone marrow cells from a mouse model of WHIM syndrome. These results suggest that CXCR4 knockdown may be a useful strategy to enhance bone marrow engraftment in the absence of toxic bone marrow conditioning regimens.

Dataset Information

Ninjurins 1 Regulate Hematopoietic Stem Cell Amplification Through Canonical WNT Signaling Independently of Plasma Membrane Rupture Activity

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets