Sulfatase modifying factor 1-mediated fibroblast growth factor signaling primes hematopoietic multilineage development

Mario Buono, Ilaria Visigalli, Roberta Bergamasco, Alessandra Biffi, Maria Pia Cosma

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 β-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.

Original languageEnglish
Pages (from-to)1647-1660
Number of pages14
JournalJournal of Experimental Medicine
Volume207
Issue number8
DOIs
Publication statusPublished - Aug 2 2010

Fingerprint

Sulfatases
Fibroblast Growth Factor 1
Hematopoietic Stem Cells
Fibroblast Growth Factors
Heparan Sulfate Proteoglycans
Multiple Sulfatase Deficiency Disease
Catenins
Erythroblasts
Wnt Signaling Pathway
B-Lymphoid Precursor Cells
Extracellular Signal-Regulated MAP Kinases
Myeloid Cells
Cell Differentiation
B-Lymphocytes
Transplantation
Tissue Donors
T-Lymphocytes
Phenotype

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Sulfatase modifying factor 1-mediated fibroblast growth factor signaling primes hematopoietic multilineage development. / Buono, Mario; Visigalli, Ilaria; Bergamasco, Roberta; Biffi, Alessandra; Cosma, Maria Pia.

In: Journal of Experimental Medicine, Vol. 207, No. 8, 02.08.2010, p. 1647-1660.

Research output: Contribution to journalArticle

Buono, Mario ; Visigalli, Ilaria ; Bergamasco, Roberta ; Biffi, Alessandra ; Cosma, Maria Pia. / Sulfatase modifying factor 1-mediated fibroblast growth factor signaling primes hematopoietic multilineage development. In: Journal of Experimental Medicine. 2010 ; Vol. 207, No. 8. pp. 1647-1660.
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