| First Author | Myllymäki MN | Year | 2017 |
| Journal | Mol Cell Biol | Volume | 37 |
| Issue | 2 | PubMed ID | 27821476 |
| Mgi Jnum | J:244936 | Mgi Id | MGI:5913715 |
| Doi | 10.1128/MCB.00529-16 | Citation | Myllymaki MN, et al. (2017) Notch Downregulation and Extramedullary Erythrocytosis in Hypoxia-Inducible Factor Prolyl 4-Hydroxylase 2-Deficient Mice. Mol Cell Biol 37(2) |
| abstractText | 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 HIFalpha 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-1alpha and HIF-2alpha were stabilized in the spleens, while the Notch ligand genes Jag1, Jag2, and Dll1 and target Hes1 became downregulated upon aging HIF-2alpha dependently. Inhibition of Notch signaling in wild-type spleen HSCs phenocopied the increased BFU-E growth. HIFalpha stabilization can thus mediate non-erythropoietin-driven splenic erythropoiesis via altered Notch signaling. |
