Endocytosis of the thrombopoietin receptor Mpl regulates megakaryocyte and erythroid maturation in mice.

Autor:	Eaton N; Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, WI, United States.; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States., Boyd EK; Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, WI, United States.; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States., Biswas R; Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, WI, United States., Lee-Sundlov MM; Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, WI, United States., Dlugi TA; Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, WI, United States., Ramsey HE; Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Pediatrics, Harvard Medical School, Boston, MA, United States., Zheng S; Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, WI, United States., Burns RT; Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, WI, United States., Sola-Visner MC; Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, United States.; Department of Pediatrics, Harvard Medical School, Boston, MA, United States., Hoffmeister KM; Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, WI, United States.; Departments of Medicine and Biochemistry, Medical College of Wisconsin, Milwaukee, WI, United States., Falet H; Translational Glycomics Center, Versiti Blood Research Institute, Milwaukee, WI, United States.; Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2022 Aug 30; Vol. 12, pp. 959806. Date of Electronic Publication: 2022 Aug 30 (Print Publication: 2022).
DOI:	10.3389/fonc.2022.959806
Abstrakt:	Dnm2 fl/fl Pf4-Cre ( Dnm2 Plt-/- ) mice lacking the endocytic GTPase dynamin 2 (DNM2) in platelets and megakaryocytes (MKs) develop hallmarks of myelofibrosis. At the cellular level, the tyrosine kinase JAK2 is constitutively active but decreased in expression in Dnm2 Plt-/- platelets. Additionally, Dnm2 Plt-/- platelets cannot endocytose the thrombopoietin (TPO) receptor Mpl, leading to elevated circulating TPO levels. Here, we assessed whether the hyperproliferative phenotype of Dnm2 Plt-/- mice was due to JAK2 constitutive activation or to elevated circulating TPO levels. In unstimulated Dnm2 Plt-/- platelets, STAT3 and, to a lower extent, STAT5 were phosphorylated, but their phosphorylation was slowed and diminished upon TPO stimulation. We further crossed Dnm2 Plt-/- mice in the Mpl -/- background to generate Mpl -/- Dnm2 Plt-/- mice lacking Mpl ubiquitously and DNM2 in platelets and MKs. Mpl -/- Dnm2 Plt-/- platelets had severely reduced JAK2 and STAT3 but normal STAT5 expression. Mpl -/- Dnm2 Plt-/- mice had severely reduced bone marrow MK and hematopoietic stem and progenitor cell numbers. Additionally, Mpl -/- Dnm2 Plt-/- mice had severe erythroblast (EB) maturation defects, decreased expression of hemoglobin and heme homeostasis genes and increased expression of ribosome biogenesis and protein translation genes in spleen EBs, and developed anemia with grossly elevated plasma erythropoietin (EPO) levels, leading to early fatality by postnatal day 25. Mpl -/- Dnm2 Plt+/+ mice had impaired EB development at three weeks of age, which normalized with adulthood. Together, the data shows that DNM2-dependent Mpl-mediated endocytosis in platelets and MKs is required for steady-state hematopoiesis and provides novel insights into a developmentally controlled role for Mpl in normal erythropoiesis, regulating hemoglobin and heme production. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Eaton, Boyd, Biswas, Lee-Sundlov, Dlugi, Ramsey, Zheng, Burns, Sola-Visner, Hoffmeister and Falet.)
Databáze:	MEDLINE
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