Document Detail

Silencing of RhoA nucleotide exchange factor, ARHGEF3, reveals its unexpected role in iron uptake.
MedLine Citation:
PMID:  21715309     Owner:  NLM     Status:  MEDLINE    
Genomewide association meta-analysis studies have identified > 100 independent genetic loci associated with blood cell indices, including volume and count of platelets and erythrocytes. Although several of these loci encode known regulators of hematopoiesis, the mechanism by which most sequence variants exert their effect on blood cell formation remains elusive. An example is the Rho guanine nucleotide exchange factor, ARHGEF3, which was previously implicated by genomewide association meta-analysis studies in bone cell biology. Here, we report on the unexpected role of ARHGEF3 in regulation of iron uptake and erythroid cell maturation. Although early erythroid differentiation progressed normally, silencing of arhgef3 in Danio rerio resulted in microcytic and hypochromic anemia. This was rescued by intracellular supplementation of iron, showing that arhgef3-depleted erythroid cells are fully capable of hemoglobinization. Disruption of the arhgef3 target, RhoA, also produced severe anemia, which was, again, corrected by iron injection. Moreover, silencing of ARHGEF3 in erythromyeloblastoid cells K562 showed that the uptake of transferrin was severely impaired. Taken together, this is the first study to provide evidence for ARHGEF3 being a regulator of transferrin uptake in erythroid cells, through activation of RHOA.
Jovana Serbanovic-Canic; Ana Cvejic; Nicole Soranzo; Derek L Stemple; Willem H Ouwehand; Kathleen Freson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-06-28
Journal Detail:
Title:  Blood     Volume:  118     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-04     Completed Date:  2012-01-09     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4967-76     Citation Subset:  AIM; IM    
Department of Haematology, University of Cambridge and NHS Blood and Transplant, Cambridge, UK.
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MeSH Terms
Anemia, Iron-Deficiency / genetics
Animals, Genetically Modified
Disease Models, Animal
Embryo, Nonmammalian
Gene Silencing / physiology*
Guanine Nucleotide Exchange Factors / antagonists & inhibitors,  genetics*,  physiology*
Iron / metabolism*
K562 Cells
Metabolic Networks and Pathways / genetics
Receptors, Transferrin / genetics,  metabolism,  physiology
rhoA GTP-Binding Protein / metabolism
Grant Support
WT 077037/Z/05/Z//Wellcome Trust; WT077047/Z/05/Z//Wellcome Trust; WT082597/Z/07/Z//Wellcome Trust
Reg. No./Substance:
0/Guanine Nucleotide Exchange Factors; 0/Receptors, Transferrin; 0/rho guanine nucleotide exchange factors; 7439-89-6/Iron; EC GTP-Binding Protein

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