title: Silencing of RhoA nucleotide exchange factor, ARHGEF3, reveals its unexpected role in iron uptake.
abstract: 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.
authors.affiliation: Department of Haematology, University of Cambridge and NHS Blood and Transplant, Cambridge, UK.
authors.forename: Jovana
authors.initials: J
authors.lastname: Serbanovic-Canic
authors.forename: Ana
authors.initials: A
authors.lastname: Cvejic
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stemple
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: Kathleen
authors.initials: K
authors.lastname: Freson
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian; D020868:Gene Silencing / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D020014:K562 Cells; D053858:Metabolic Networks and Pathways / Q000235:genetics; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D064067:Rho Guanine Nucleotide Exchange Factors; D015027:Zebrafish; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C576601:ARHGEF3 protein, human; D020662:Guanine Nucleotide Exchange Factors; D011990:Receptors, Transferrin; D064067:Rho Guanine Nucleotide Exchange Factors; D007501:Iron; D020742:rhoA GTP-Binding Protein