Notch downregulation and extramedullary erythrocytosis in hypoxia-inducible factor prolyl 4-hydroxylase 2-deficient mice
Myllymäki, Mikko N. M.; Määttä, Jenni; Dimova, Elitsa Y.; Izzi, Valerio; Väisänen, Timo; Myllyharju, Johanna; Koivunen, Peppi; Serpi, Raisa (2016-11-07)
Myllymäki MNM, Määttä J, Dimova EY, Izzi V, Väisänen T, Myllyharju J, Koivunen P, Serpi R. 2017. Notch downregulation and extramedullary erythrocytosis in hypoxia-inducible factor prolyl 4-hydroxylase 2-deficient mice. Mol Cell Biol 37:e00529-16. https://doi.org/10.1128/MCB.00529-16
Copyright © 2017 American Society for Microbiology. All Rights Reserved. Published in this repository with the kind permission of the publisher.
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.
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