PUBLICATION

Glia maturation factor-γ is required for initiation and maintenance of hematopoietic stem and progenitor cells

Authors
Li, H., Luo, Q., Cai, S., Tie, R., Meng, Y., Shan, W., Xu, Y., Zeng, X., Qian, P., Huang, H.
ID
ZDB-PUB-230501-40
Date
2023
Source
Stem Cell Research & Therapy   14: 117117 (Journal)
Registered Authors
Keywords
Blood flow, Glia maturation factor-?, HSPC, Notch, Yap, Zebrafish
MeSH Terms
  • Animals
  • Glia Maturation Factor*/genetics
  • Glia Maturation Factor*/metabolism
  • Zebrafish Proteins/genetics
  • Hematopoietic Stem Cells/metabolism
  • Zebrafish*/genetics
  • Zebrafish*/metabolism
(all 7)
PubMed
37122014 Full text @ Stem Cell Res. Ther.
Abstract
Background In vertebrates, hematopoietic stem and progenitor cells (HSPCs) emerge from hemogenic endothelium in the floor of the dorsal aorta and subsequently migrate to secondary niches where they expand and differentiate into committed lineages. Glia maturation factor γ (gmfg) is a key regulator of actin dynamics that was shown to be highly expressed in hematopoietic tissue. Our goal is to investigate the role and mechanism of gmfg in embryonic HSPC development.
Methods In-depth bioinformatics analysis of our published RNA-seq data identified gmfg as a cogent candidate gene implicated in HSPC development. Loss and gain-of-function strategies were applied to study the biological function of gmfg. Whole-mount in situ hybridization, confocal microscopy, flow cytometry, and western blotting were used to evaluate changes in the number of various hematopoietic cells and expression levels of cell proliferation, cell apoptosis and hematopoietic-related markers. RNA-seq was performed to screen signaling pathways responsible for gmfg deficiency-induced defects in HSPC initiation. The effect of gmfg on YAP sublocalization was assessed in vitro by utilizing HUVEC cell line.
Results We took advantage of zebrafish embryos to illustrate that loss of gmfg impaired HSPC initiation and maintenance. In gmfg-deficient embryos, the number of hemogenic endothelium and HSPCs was significantly reduced, with the accompanying decreased number of erythrocytes, myelocytes and lymphocytes. We found that blood flow modulates gmfg expression and gmfg overexpression could partially rescue the reduction of HSPCs in the absence of blood flow. Assays in zebrafish and HUVEC showed that gmfg deficiency suppressed the activity of YAP, a well-established blood flow mediator, by preventing its shuttling from cytoplasm to nucleus. During HSPC initiation, loss of gmfg resulted in Notch inactivation and the induction of Notch intracellular domain could partially restore the HSPC loss in gmfg-deficient embryos.
Conclusions We conclude that gmfg mediates blood flow-induced HSPC maintenance via regulation of YAP, and contributes to HSPC initiation through the modulation of Notch signaling. Our findings reveal a brand-new aspect of gmfg function and highlight a novel mechanism for embryonic HSPC development.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
cz3325TgTransgenic Insertion
    jh11TgTransgenic Insertion
      kca3TgTransgenic Insertion
        kca4TgTransgenic Insertion
          la2TgTransgenic Insertion
            nz50TgTransgenic Insertion
              s896TgTransgenic Insertion
                y1TgTransgenic Insertion
                  zf169TgTransgenic Insertion
                    1 - 9 of 9
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                    Human Disease / Model
                    No data available
                    Sequence Targeting Reagents
                    Target Reagent Reagent Type
                    gmfbMO1-gmfbMRPHLNO
                    gmfgMO1-gmfgMRPHLNO
                    gmfgMO2-gmfgMRPHLNO
                    tnnt2aMO3-tnnt2aMRPHLNO
                    1 - 4 of 4
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                    Fish
                    No data available
                    Antibodies
                    No data available
                    Orthology
                    No data available
                    Engineered Foreign Genes
                    Marker Marker Type Name
                    DsRed2EFGDsRed2
                    EGFPEFGEGFP
                    GAL4EFGGAL4
                    mCherryEFGmCherry
                    1 - 4 of 4
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                    Mapping
                    No data available
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                    Citation
                    Li, H., Luo, Q., Cai, S., Tie, R., Meng, Y., Shan, W., Xu, Y., Zeng, X., Qian, P., Huang, H. (2023) Glia maturation factor-γ is required for initiation and maintenance of hematopoietic stem and progenitor cells. Stem Cell Research & Therapy. 14:117117.