Developmental regulation of myeloerythroid progenitor function by the Lin28b–let-7–Hmga2 axis
| Autor: | R. Grant Rowe, Amy J. Wagers, Samantha J. Ross, Leo D. Wang, George Q. Daley, Silvia Coma, Ronald Mathieu, Phi T. Nguyen, Patricia Sousa, Areum Han, Antony Rodriguez, Daniel S. Pearson |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Immunology Morphogenesis Biology LIN28 Article Mice 03 medical and health sciences Animals Immunology and Allergy Erythropoiesis Research Articles Myeloid Progenitor Cells Progenitor Mice Knockout Regulation of gene expression Innate immune system Effector HMGA2 Protein Gene Expression Regulation Developmental RNA-Binding Proteins Cell biology DNA-Binding Proteins MicroRNAs Haematopoiesis 030104 developmental biology Heterochrony |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Daley and collaborators show that endogenous Lin28b drives erythroid-dominant fetal hematopoiesis and that decreases in Lin28b activate adult granulocyte-predominant hematopoiesis. 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. |
| Databáze: | OpenAIRE |
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