title: Developmental regulation of myeloerythroid progenitor function by the Lin28b-let-7-Hmga2 axis.
abstract: For appropriate development, tissue and organ system morphogenesis and maturation must occur in synchrony with the overall developmental requirements of the host. Mistiming of such developmental events often results in disease. The hematopoietic system matures from the fetal state, characterized by robust erythrocytic output that supports prenatal growth in the hypoxic intrauterine environment, to the postnatal state wherein granulocytes predominate to provide innate immunity. Regulation of the developmental timing of these myeloerythroid states is not well understood. In this study, we find that expression of the heterochronic factor Lin28b decreases in common myeloid progenitors during hematopoietic maturation to adulthood in mice. This decrease in Lin28b coincides with accumulation of mature let-7 microRNAs, whose biogenesis is regulated by Lin28 proteins. We find that inhibition of let-7 in the adult hematopoietic system recapitulates fetal erythroid-dominant hematopoiesis. Conversely, deletion of Lin28b or ectopic activation of let-7 microRNAs in the fetal state induces a shift toward adult-like myeloid-dominant output. Furthermore, we identify Hmga2 as an effector of this genetic switch. These studies provide the first detailed analysis of the roles of endogenous Lin28b and let-7 in the timing of hematopoietic states during development.
authors.affiliation: Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: R Grant
authors.initials: RG
authors.lastname: Rowe
authors.affiliation: Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02215 Harvard Stem Cell Institute, Cambridge, MA 02138 Joslin Diabetes Center, Boston, MA 02215.
authors.forename: Leo D
authors.initials: LD
authors.lastname: Wang
authors.affiliation: Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: Silvia
authors.initials: S
authors.lastname: Coma
authors.affiliation: Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02215 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
authors.forename: Areum
authors.identifier: 0000-0001-5949-4672
authors.initials: A
authors.lastname: Han
authors.affiliation: Harvard Stem Cell Institute, Cambridge, MA 02138 Flow Cytometry Laboratory, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Ronald
authors.identifier: 0000-0002-7625-0239
authors.initials: R
authors.lastname: Mathieu
authors.affiliation: Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pearson
authors.affiliation: Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: Samantha
authors.identifier: 0000-0002-2804-1635
authors.initials: S
authors.lastname: Ross
authors.affiliation: Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02215.
authors.forename: Patricia
authors.identifier: 0000-0001-6153-9518
authors.initials: P
authors.lastname: Sousa
authors.affiliation: Harvard Stem Cell Institute, Cambridge, MA 02138 Joslin Diabetes Center, Boston, MA 02215.
authors.forename: Phi T
authors.initials: PT
authors.lastname: Nguyen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Antony
authors.identifier: 0000-0001-7184-9413
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: Harvard Stem Cell Institute, Cambridge, MA 02138 Joslin Diabetes Center, Boston, MA 02215 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.affiliation: Stem Cell Transplantation Program, Stem Cell Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02215 Harvard Stem Cell Institute, Cambridge, MA 02138 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 Howard Hughes Medical Institute, Boston, MA 02115 Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115 Manton Center for Orphan Disease Research, Boston, MA 02115 george.daley@childrens.harvard.edu.
authors.forename: George Q
authors.identifier: 0000-0002-6346-5919
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004920:Erythropoiesis / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D025743:HMGA2 Protein / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D016601:RNA-Binding Proteins
chemical_list: D004268:DNA-Binding Proteins; D025743:HMGA2 Protein; C570876:Lin28b protein, mouse; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C542687:mirnlet7 microRNA, mouse