ZFP36L2 is required for self-renewal of early burst-forming unit erythroid progenitors

Zhang, L., Prak, L., Rayon-Estrada, V., Thiru, P., Flygare, J., Lim, B., Lodish, H. F. (2013) ZFP36L2 is required for self-renewal of early burst-forming unit erythroid progenitors. Nature, 499 (7456). pp. 92-6. ISSN 1476-4687 (Electronic)0028-0836 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/23748442
DOI: 10.1038/nature12215

Abstract

Stem cells and progenitors in many lineages undergo self-renewing divisions, but the extracellular and intracellular proteins that regulate this process are largely unknown. Glucocorticoids stimulate red blood cell formation by promoting self-renewal of early burst-forming unit-erythroid (BFU-E) progenitors. Here we show that the RNA-binding protein ZFP36L2 is a transcriptional target of the glucocorticoid receptor (GR) in BFU-Es and is required for BFU-E self-renewal. ZFP36L2 is normally downregulated during erythroid differentiation from the BFU-E stage, but its expression is maintained by all tested GR agonists that stimulate BFU-E self-renewal, and the GR binds to several potential enhancer regions of ZFP36L2. Knockdown of ZFP36L2 in cultured BFU-E cells did not affect the rate of cell division but disrupted glucocorticoid-induced BFU-E self-renewal, and knockdown of ZFP36L2 in transplanted erythroid progenitors prevented expansion of erythroid lineage progenitors normally seen following induction of anaemia by phenylhydrazine treatment. ZFP36L2 preferentially binds to messenger RNAs that are induced or maintained at high expression levels during terminal erythroid differentiation and negatively regulates their expression levels. ZFP36L2 therefore functions as part of a molecular switch promoting BFU-E self-renewal and a subsequent increase in the total numbers of colony-forming unit-erythroid (CFU-E) progenitors and erythroid cells that are generated.

Item Type: Paper
Uncontrolled Keywords: Animals Cell Count Cell Division/drug effects Cell Lineage Down-Regulation Erythroid Precursor Cells/ cytology/ metabolism Erythropoiesis/genetics Gene Knockdown Techniques Glucocorticoids/pharmacology Mice RNA, Messenger/genetics/metabolism RNA-Binding Proteins/metabolism Receptors, Glucocorticoid/agonists/metabolism Stress, Physiological Tristetraprolin/deficiency/genetics/ metabolism
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell differentiation
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell differentiation > erythropoiesis
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > progenitor cell
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > progenitor cell
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > progenitor cell

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > RNA binding protein
CSHL Authors:
Communities: CSHL labs > Zhang L. lab
Depositing User: Matt Covey
Date Deposited: 13 Jul 2015 17:00
Last Modified: 13 Jul 2015 17:00
PMCID: PMC3702661
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31618

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