Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 213, Issue 8, Pages 1497-1512Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20151912
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Funding
- US National Institutes of Health: National Institute for Diabetes and Digestive and Kidney Diseases [R24-DK092760, R24-DK49216]
- US National Institutes of Health: National Heart, Lung, and Blood Institute (NHBLI Progenitor Cell Biology Consortium) [UO1-HL100001]
- US National Institutes of Health: National Institute of General Medical Sciences [RO1GM107536, PN2 EY018244, P30DK036836]
- NHLBI [5T32HL007574-34]
- Damon Runyon-Sohn Foundation Pediatric Cancer Research fellowship [DSRG 02-12]
- Alex's Lemonade Stand Foundation for Childhood Cancer Young Investigator award [31582]
- St. Baldrick's Foundation PALS Scholar award [243625]
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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.
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