9 research outputs found
ZFP36L2 is required for self-renewal of early burst-forming unit erythroid progenitors
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 unitâerythroid (BFUâE) progenitors. Here we show that the RNA-binding protein ZFP36L2 is a transcriptional target of the glucocorticoid receptor (GR) in BFUâEs and is required for BFUâE self-renewal. ZFP36L2 is normally downregulated during erythroid differentiation from the BFUâE stage, but its expression is maintained by all tested GR agonists that stimulate BFUâE self-renewal, and the GR binds to several potential enhancer regions of ZFP36L2. Knockdown of ZFP36L2 in cultured BFUâE cells did not affect the rate of cell division but disrupted glucocorticoid-induced BFUâE 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 BFUâE self-renewal and a subsequent increase in the total numbers of colony-forming unitâerythroid (CFUâE) progenitors and erythroid cells that are generated.National Institutes of Health (U.S.) (Grant P01 HL 32262