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

The Journal of Experimental Medicine
Mario BuonoMaria Pia Cosma

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 diffe...Continue Reading

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Citations

Jan 5, 2013·The Journal of Biological Chemistry·Eva C EnnemannThomas Dierks
Feb 12, 2014·Immunology Letters·Vishal J SindhavaMichael P Cancro
Aug 28, 2018·Journal of Cellular Physiology·Sohini Chakraborty, Zhumur Ghosh
Oct 2, 2012·Nature·Joe V ChakkalakalAndrew S Brack
Sep 20, 2018·BioMed Research International·P J E UijtdewilligenT H van Kuppevelt
Jun 4, 2017·Glycoconjugate Journal·Dulce Papy-Garcia, Patricia Albanese
Jun 23, 2021·Yeungnam University Journal of Medicine·Hyun-Je KimYoung-Hoon Hong

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Methods Mentioned

BETA
transgenic
PCR
FACS
flow cytometry

Software Mentioned

Applied
PrimerExpress
Biosystems SDS

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