Dyrk-3 Kinase Is an Erythroid Cell-Intrinsic Attenuator of Stress Erythropoiesis.

During anemia, red cell production depends critically upon erythropoietin and is also supported by Gas-6, oncostatin-M, and BMP4/Madh5 as recently characterized stress erythropoietic factors. Considerably less is understood concerning factors that limit this process. Via gene disruption, and as studied in four functional paradigms, stress erythropoiesis presently is shown to be attenuated by Dyrk-3 kinase. Tissue-wide RT-PCR analyses confirmed Dyrk-3 expression selectively in erythroid progenitor cells, and testes. In Dyrk-3^−/− mice, reproductive capacity and steady-state hematopoiesis were normal (with the exception of modest decreases in splenic BFUe). In response to phenylhydrazine- induced anemia, however, reticulocyte production in the absence of Dyrk-3 was sustained, and was elevated to 270% of wild-type controls. Reticulocyte levels (and hematocrits) in Dyrk-3^−/− mice also were elevated significantly over controls following 5′-fluorouracil- induced anemia, and a two-fold advantage for Dyrk-3^−/− CD71^highTer119^pos cell formation was observed in short-term bone marrow transplant experiments. These outcomes indicated enhanced rates of Dyrk-3^−/− erythroblast development, and using a unique medullary erythroblast expansion system, accelerated development of Dyrk-3^−/− Kit^pos proerythroblasts to maturing CD71^high Ter119^pos cells was observed. Given these data, Dyrk-3 is proposed to selectively limit (and possibly apportion) red cell production during stress erythropoiesis.