Rasa3 regulates stage-specific cell cycle progression in murine erythropoiesis
| Autor: | Steven L. Ciciotte, Lionel Blanc, Theodosia A. Kalfa, Julien Papoin, Elena C. Brindley, Raymond F. Robledo, Luanne L. Peters, Lauren Kennedy |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Mutation Missense Biology Article 03 medical and health sciences 0302 clinical medicine Erythroid Cells hemic and lymphatic diseases medicine Missense mutation Animals Erythropoiesis Progenitor cell Molecular Biology Loss function Cells Cultured Mice Inbred BALB C Cell Cycle GTPase-Activating Proteins Cell Biology Hematology Cell cycle Phenotype Haematopoiesis 030104 developmental biology medicine.anatomical_structure Cancer research ras Proteins Molecular Medicine Bone marrow 030215 immunology |
| Zdroj: | Blood Cells Mol Dis |
| ISSN: | 1096-0961 |
| Popis: | Inherited bone marrow failure syndromes (IBMFS) are heterogeneous disorders characterized by dysregulated hematopoiesis in various lineages, developmental anomalies, and predisposition to malignancy. The scat (severe combined anemia and thrombocytopenia) mouse model is a model of IBMFS with a phenotype of pancytopenia cycling through crises and remission. Scat carries an autosomal recessive missense mutation in Rasa3 that results in RASA3 mislocalization and loss of function. RASA3 functions as a Ras-GTPase activating protein (GAP), and its loss of function in scat results in increased erythroid RAS activity and reactive oxygen species (ROS) and altered erythroid cell cycle progression, culminating in delayed terminal erythroid differentiation. Here we sought to further resolve the erythroid cell cycle defect in scat through ex vivo flow cytometric analyses. These studies revealed a specific G0/G1 accumulation in scat bone marrow (BM) polychromatophilic erythroblasts and scat BM Ter119(−)/c-KIT(+)/CD71(lo/med) progenitors, with no changes evident in equivalent scat spleen populations. Systematic analyses of RNAseq data from megakaryocyte-erythroid progenitors (MEPs) in scat crisis vs. scat partial remission reveal altered expression of genes involved in the G1-S checkpoint. Together, these data indicate a precise, biphasic role for RASA3 in regulating the cell cycle during erythropoiesis with relevance to hematopoietic disease progression. |
| Databáze: | OpenAIRE |
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