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

Under stress conditions such as acute blood loss or chronic anaemia, glucocorticoids trigger self-renewal of early burst-forming unit–erythroid (BFU–E) progenitors in the spleen, however, the mechanism of glucocorticoid action is not well understood; here the RNA binding protein ZFP36L2 is identified as a transcriptional target of the glucocorticoid receptor in BFU-Es and is shown to be involved in the process of erythroid cell expansion following exposure to glucocorticoids. Control of erythroid cell self-renewal Although considerable progress has been made in the understanding of self-renewal of embryonic stem and iPS cells, much less is known about the intracellular signalling proteins that regulate self-renewal of stem and progenitor cells in adult animals. Under stress conditions such as acute blood loss or chronic anaemia, glucocorticoids trigger self-renewal of erythroid burst-forming unit–erythrocyte (BFU–E) progenitors in the spleen, leading to increased numbers of self-renewal divisions. Harvey Lodish and colleagues have now identified the RNA-binding protein ZFP36l2 as a transcriptional target of the glucocorticoid receptor in BFU–Es, and show that it is involved in the process of erythroid cell expansion following exposure to glucocorticoids. 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 1 , 2 , 3 , 4 . 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 ne