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
Notch downregulation and extramedullary erythrocytosis in hypoxia-inducible factor prolyl 4-hydroxylase 2-deficient mice
|Author:||Myllymäki, Mikko N. M.1; Määttä, Jenni1; Dimova, Elitsa Y.1;|
1Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu
2Department of Pathology, Oulu University Hospital, and Department of Pathology, Cancer and Translational Medicine Research Unit, University of Oulu
|Online Access:||PDF Full Text (PDF, 1.8 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe201803276197
American Society for Microbiology,
|Publish Date:|| 2018-03-27
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.
Molecular and cellular biology
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
This study was supported by Academy of Finland grants 218129 (Peppi Koivunen) and Center of Excellence 2012-2017 grant 251314 (Johanna Myllyharju) and by the S. Jusélius Foundation (Peppi Koivunen and Johanna Myllyharju), the Emil Aaltonen Foundation (Peppi Koivunen), the Jane and Aatos Erkko Foundation (Peppi Koivunen and Johanna Myllyharju), and FibroGen Inc. (Johanna Myllyharju).
|Academy of Finland Grant Number:||
218129 (Academy of Finland Funding decision)
251314 (Academy of Finland Funding decision)
Copyright © 2017 American Society for Microbiology. All Rights Reserved. Published in this repository with the kind permission of the publisher.