Abstract
Self-renewal and differentiation of hematopoietic stem cells (HSCs) are balanced by the concerted activities of the fibroblast growth factor (FGF), Wnt, and Notch pathways, which are tuned by enzyme-mediated remodeling of heparan sulfate proteoglycans (HSPGs). Sulfatase modifying factor 1 (SUMF1) activates the Sulf1 and Sulf2 sulfatases that remodel the HSPGs, and is mutated in patients with multiple sulfatase deficiency. Here, we show that the FGF signaling pathway is constitutively activated in Sumf1(-/-) HSCs and hematopoietic stem progenitor cells (HSPCs). These cells show increased p-extracellular signal-regulated kinase levels, which in turn promote beta-catenin accumulation. Constitutive activation of FGF signaling results in a block in erythroid differentiation at the chromatophilic erythroblast stage, and of B lymphocyte differentiation at the pro-B cell stage. A reduction in mature myeloid cells and an aberrant development of T lymphocytes are also seen. These defects are rescued in vivo by blocking the FGF pathway in Sumf1(-/-) mice. Transplantation of Sumf1(-/-) HSPCs into wild-type mice reconstituted the phenotype of the donors, suggesting a cell autonomous defect. These data indicate that Sumf1 controls HSPC differentiation and hematopoietic lineage development through FGF and Wnt signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animal Structures / cytology
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Animals
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Antigens, CD / metabolism
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Bone Marrow Cells / cytology
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Bone Marrow Cells / metabolism
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Butadienes / pharmacology
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CCAAT-Enhancer-Binding Protein-alpha / genetics
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CCAAT-Enhancer-Binding Protein-alpha / metabolism
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Colony-Forming Units Assay
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Erythropoiesis / drug effects
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Erythropoiesis / physiology
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fibroblast Growth Factors / antagonists & inhibitors
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Fibroblast Growth Factors / physiology*
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GATA1 Transcription Factor / genetics
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GATA1 Transcription Factor / metabolism
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Gene Expression / drug effects
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Gene Expression / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Hematopoiesis / drug effects
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Hematopoiesis / physiology*
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Hematopoietic Stem Cell Transplantation
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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Lymphopoiesis / drug effects
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Lymphopoiesis / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myelopoiesis / drug effects
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Myelopoiesis / physiology
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Nitriles / pharmacology
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Oxidoreductases Acting on Sulfur Group Donors
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Phosphorylation / drug effects
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Phosphorylation / genetics
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Protein Kinase Inhibitors / pharmacology
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Pyrroles / pharmacology
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Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors
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Receptor, Notch1 / genetics
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Stem Cells / cytology
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Stem Cells / metabolism
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Sulfatases / genetics*
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Sulfatases / metabolism
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Sulfotransferases / genetics
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Sulfotransferases / metabolism
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Wnt Proteins / physiology
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beta Catenin / metabolism
Substances
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Antigens, CD
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Butadienes
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CCAAT-Enhancer-Binding Protein-alpha
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GATA1 Transcription Factor
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Gata1 protein, mouse
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Nitriles
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Notch1 protein, mouse
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Protein Kinase Inhibitors
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Pyrroles
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Receptor, Notch1
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SU 5402
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U 0126
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Wnt Proteins
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beta Catenin
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Fibroblast Growth Factors
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Oxidoreductases Acting on Sulfur Group Donors
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Receptor, Fibroblast Growth Factor, Type 1
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Glycogen Synthase Kinase 3 beta
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Extracellular Signal-Regulated MAP Kinases
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Glycogen Synthase Kinase 3
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Sulf1 protein, mouse
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Sulfotransferases
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SUMF1 protein, human
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Sulf2 protein, mouse
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Sulfatases