title: Dicer1 deletion in myeloid-committed progenitors causes neutrophil dysplasia and blocks macrophage/dendritic cell development in mice.
abstract: MicroRNAs (miRNAs) have the potential to regulate cellular differentiation programs; however, miRNA deficiency in primary hematopoietic stem cells (HSCs) results in HSC depletion in mice, leaving the question of whether miRNAs play a role in early-lineage decisions un-answered. To address this issue, we deleted Dicer1, which encodes an essential RNase III enzyme for miRNA biogenesis, in murine CCAAT/enhancer-binding protein α (C/EBPA)-positive myeloid-committed progenitors in vivo. In contrast to the results in HSCs, we found that miRNA depletion affected neither the number of myeloid progenitors nor the percentage of C/EBPA-positive progenitor cells. Analysis of gene-expression profiles from wild-type and Dicer1-deficient granulocyte-macrophage progenitors (GMPs) revealed that 20 miRNA families were active in GMPs. Of the derepressed miRNA targets in Dicer1-null GMPs, 27% are normally exclusively expressed in HSCs or are specific for multipotent progenitors and erythropoiesis, indicating an altered gene-expression landscape. Dicer1-deficient GMPs were defective in myeloid development in vitro and exhibited an increased replating capacity, indicating the regained self-renewal potential of these cells. In mice, Dicer1 deletion blocked monocytic differentiation, depleted macrophages, and caused myeloid dysplasia with morphologic features of Pelger-Huët anomaly. These results provide evidence for a miRNA-controlled switch for a cellular program of self-renewal and expansion toward myeloid differentiation in GMPs.
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Dr Molewaterplein 50, Rotterdam, The Netherlands.
authors.forename: Mir Farshid
authors.initials: MF
authors.lastname: Alemdehy
authors.forename: Nicole G J A
authors.initials: NG
authors.lastname: van Boxtel
authors.forename: Hans W J
authors.initials: HW
authors.lastname: de Looper
authors.forename: Iris J
authors.initials: IJ
authors.lastname: van den Berge
authors.forename: Mathijs A
authors.initials: MA
authors.lastname: Sanders
authors.forename: Tom
authors.initials: T
authors.lastname: Cupedo
authors.forename: Ivo P
authors.initials: IP
authors.lastname: Touw
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Erkeland
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D004622:Embryo, Mammalian; D017353:Gene Deletion; D007958:Leukocyte Count; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D010381:Pelger-Huet Anomaly / Q000235:genetics / Q000473:pathology; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases