title: Dicer is selectively important for the earliest stages of erythroid development.
abstract: MicroRNAs (miRs) are involved in many aspects of normal and malignant hematopoiesis, including hematopoietic stem cell (HSC) self-renewal, proliferation, and terminal differentiation. However, a role for miRs in the generation of the earliest stages of lineage committed progenitors from HSCs has not been identified. Using Dicer inactivation, we show that the miR complex is not only essential for HSC maintenance but is specifically required for their erythroid programming and subsequent generation of committed erythroid progenitors. In bipotent pre-MegEs, loss of Dicer up-regulated transcription factors preferentially expressed in megakaryocyte progenitors (Gata2 and Zfpm1) and decreased expression of the erythroid-specific Klf1 transcription factor. These results show a specific requirement for Dicer in acquisition of erythroid lineage programming and potential in HSCs and their subsequent erythroid lineage differentiation, and in particular indicate a role for the miR complex in achieving proper balance of lineage-specific transcriptional regulators necessary for HSC multilineage potential to be maintained.
authors.affiliation: Haematopoietic Stem Cell Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Natalija
authors.initials: N
authors.lastname: Buza-Vidas
authors.forename: Valeriu B
authors.initials: VB
authors.lastname: Cismasiu
authors.forename: Susan
authors.initials: S
authors.lastname: Moore
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Mead
authors.forename: Petter S
authors.initials: PS
authors.lastname: Woll
authors.forename: Michael
authors.initials: M
authors.lastname: Lutteropp
authors.forename: Luca
authors.initials: L
authors.lastname: Melchiori
authors.forename: Sidinh
authors.initials: S
authors.lastname: Luc
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Bouriez-Jones
authors.forename: Deborah
authors.initials: D
authors.lastname: Atkinson
authors.forename: Donal
authors.initials: D
authors.lastname: O'Carroll
authors.forename: Sten Eirik W
authors.initials: SE
authors.lastname: Jacobsen
authors.forename: Claus
authors.initials: C
authors.lastname: Nerlov
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D019070:Cell Lineage; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000502:physiology*; D041905:Erythroid Cells / Q000166:cytology* / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000037:antagonists & inhibitors / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D014157:Transcription Factors; C045073:Cre recombinase; D019426:Integrases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases