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Cellular repressor of E1A\u2010stimulated 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 <jats:italic>CREG1<\/jats:italic> expression increases progressively during erythroid differentiation. In zebrafish, <jats:italic>creg1<\/jats:italic> mRNA is preferentially expressed within the intermediate cell mass (ICM)\/peripheral blood island (PBI) region where primitive erythropoiesis occurs. Loss of <jats:italic>creg1<\/jats:italic> leads to anemia caused by defective erythroid differentiation and excessive apoptosis of erythroid progenitors. Mechanistically, <jats:italic>creg1<\/jats:italic> deficiency results in reduced activation of TGF\u2010\u03b2\/Smad2 signaling pathway. Treatment with an agonist of the Smad2 pathway (IDE2) could significantly restore the defective erythroid development in <jats:italic>creg1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mutants. Further, <jats:italic>Klf1<\/jats:italic>, identified as a key target gene downstream of the TGF\u2010\u03b2\/Smad2 signaling pathway, is involved in <jats:italic>creg1<\/jats:italic> deficiency\u2010induced 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\u2010\u03b2\/Smad2\u2010Klf1 axis. This finding may contribute to the understanding of normal erythropoiesis and the pathogenesis of erythroid disorders.<\/jats:p>","DOI":"10.1002\/advs.202402804","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T07:22:11Z","timestamp":1719904931000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Creg1 Regulates Erythroid Development via TGF\u2010\u03b2\/Smad2\u2010Klf1 Axis in Zebrafish"],"prefix":"10.1002","volume":"11","author":[{"given":"Xiao","family":"Han","sequence":"first","affiliation":[{"name":"Shanghai Institute of Hematology State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at Shanghai Ruijin Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 200025 China"},{"name":"CNRS\u2010LIA Hematology and Cancer Sino\u2010French Research Center for Life Sciences and Genomics Ruijin Hospital Shanghai Jiao Tong University 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