Creg1 Regulates Erythroid Development via TGF-β/Smad2-Klf1 Axis in Zebrafish

Understanding the regulation of normal erythroid development will help to develop new potential therapeutic strategies for disorders of the erythroid lineage. Cellular repressor of E1A-stimulated genes 1 (CREG1) is a glycoprotein that has been implicated in the regulation of tissue homeostasis. However, its role in erythropoiesis remains largely undefined. In this study, it is found that CREG1 expression increases progressively during erythroid differentiation. In zebrafish, creg1 mRNA is preferentially expressed within the intermediate cell mass (ICM)/peripheral blood island (PBI) region where primitive erythropoiesis occurs. Loss of creg1 leads to anemia caused by defective erythroid differentiation and excessive apoptosis of erythroid progenitors. Mechanistically, creg1 deficiency results in reduced activation of TGF-β/Smad2 signaling pathway. Treatment with an agonist of the Smad2 pathway (IDE2) could significantly restore the defective erythroid development in creg1^-/- mutants. Further, Klf1, identified as a key target gene downstream of the TGF-β/Smad2 signaling pathway, is involved in creg1 deficiency-induced aberrant erythropoiesis. Thus, this study reveals a previously unrecognized role for Creg1 as a critical regulator of erythropoiesis, mediated at least in part by the TGF-β/Smad2-Klf1 axis. This finding may contribute to the understanding of normal erythropoiesis and the pathogenesis of erythroid disorders.