Notch Downregulation and Extramedullary Erythrocytosis in Hypoxia-Inducible Factor Prolyl 4-Hydroxylase 2-Deficient Mice.
Erythrocytosis is driven mainly by erythropoietin, which is regulated by hypoxia-inducible factor (HIF). Mutations in HIF prolyl 4-hydroxylase 2 (HIF-P4H-2) (PHD2/EGLN1), the major downregulator of HIFα subunits, are found in familiar erythrocytosis, and large-spectrum conditional inactivation of HIF-P4H-2 in mice leads to severe erythrocytosis. Although bone marrow is the primary site for erythropoiesis, spleen remains capable of extramedullary erythropoiesis. We studied HIF-P4H-2-deficient (Hif-p4h-2gt/gt) mice, which show slightly induced erythropoiesis upon aging despite nonincreased erythropoietin levels, and identified spleen as the site of extramedullary erythropoiesis. Splenic hematopoietic stem cells (HSCs) of these mice exhibited increased erythroid burst-forming unit (BFU-E) growth, and the mice were protected against anemia. HIF-1α and HIF-2α were stabilized in the spleens, while the Notch ligand genes Jag1, Jag2, and Dll1 and target Hes1 became downregulated upon aging HIF-2α dependently. Inhibition of Notch signaling in wild-type spleen HSCs phenocopied the increased BFU-E growth. HIFα stabilization can thus mediate non-erythropoietin-driven splenic erythropoiesis via altered Notch signaling.
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
Mikko N M
MNM
Myllymäki
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
Jenni
J
Määttä
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
Elitsa Y
EY
Dimova
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
Valerio
V
Izzi
Department of Pathology, Oulu University Hospital, and Department of Pathology, Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.
Timo
T
Väisänen
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
Johanna
J
Myllyharju
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
Peppi
P
Koivunen
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland raisa.serpi@oulu.fi.
Raisa
R
Serpi
D000375:Aging / Q000473:pathology; D000740:Anemia / Q000150:complications / Q000473:pathology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001853:Bone Marrow / Q000473:pathology; D002452:Cell Count; D003114:Colony-Forming Units Assay; D015536:Down-Regulation; D015672:Erythroid Precursor Cells / Q000378:metabolism; D006965:Hyperplasia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000473:pathology; D008024:Ligands; D008297:Male; D008533:Megakaryocytes / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D011086:Polycythemia / Q000378:metabolism* / Q000473:pathology*; D055550:Protein Stability; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000473:pathology; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008024:Ligands; D051880:Receptors, Notch; D000099162:Endothelial PAS Domain-Containing Protein 1; C490189:Egln1 protein, mouse
erythrocytosis; hypoxia; hypoxia-inducible factor prolyl-4-hydroxylase 2; spleen