RED CELLS , IRON , AND ERYTHROPOIESIS Elavl 1 a regulates zebra fi sh erythropoiesis via posttranscriptional control of gata 1

During vertebrate embryogenesis, 2 sequential waves of hematopoiesis occur; they are termed primitive and definitive. In zebrafish, primitive erythropoiesis initiates in the intermediate cell mass in posterior lateral mesoderm, giving rise to erythrocytes and macrophages before 1 day postfertilization (dpf), followed by definitive hematopoiesis when stem/progenitors are produced from hemogenic endothelium in the ventral wall of the dorsal aorta. At the time of primitive erythroid cell generation, lymphocytes and granulocytes arise from an anterior lateral mesoderm domain. After 2 dpf, a major niche for hematopoiesis is present in caudal hematopoietic tissue in the tail. Eventually, the kidney serves as the major site of hematopoiesis through adulthood in the zebrafish. Gata1 is a key transcription factor that is essential for blood cell development. In addition to controlling cell survival and proliferation, Gata1 directly binds to and activates expression of erythroidspecific globin genes, the erythropoietin receptor, and its own promoter. Knockout of Gata1 in the mouse leads to embryonic lethality due to severe yolk sac anemia, consistent with a loss of primitive erythropoiesis. A zebrafish gata1 mutant has normal expression levels for markers of hematopoietic stem/progenitor, myeloid, and lymphoid cells, but a complete loss of erythroid gene expression through 24 hours postfertilization (hpf). RNA-binding proteins (RBPs) are recognized to play key regulatory roles in development, including hematopoiesis. Several RBPs bind AU-rich elements (AREs) in the 39–untranslated region (UTR), which are present in;5% to 8% of mammalian transcripts. Several distinct RBPs have been identified, including ARE-binding factor-1 (AUF1), embryonic lethal and abnormal vision (ELAV) family members, ZFP36 family members, and KH-type splicing regulatory protein (KHRP). AUF1 has 4 distinct isoforms (p37, p40, p42, and p45) and regulates many genes that are involved in hematopoiesis, for example, Bcl2 and Il8. Knockout of all 4AUF1 isoforms in mice leads to reduced numbers of splenic T and B cells, suggesting that AUF1 has an important role in lymphopoiesis. KSRP can also regulate many hematopoietic target genes, including Cxcl2, Cxcl3, Il6, and Tlr4. Recently, analysis of Zfp36L2 knockout mice showed the critical role of this RBP in self-renewal of erythroid progenitors. These studies indicate that posttranscriptional gene regulatory mechanisms are important in hematopoiesis. The ELAV family contains 4 members, the ubiquitously expressed Elavl1 (HuR, HuA), and neuronal Elavl2 (HuB), Elavl3 (HuC), and Elavl4 (HuD). Recently, ELAVL4 was also shown to be expressed in pancreatic b cells and to regulate the translation of insulin. Elavl1 has been shown to play an essential role in embryonic development and stem/progenitor cell survival in adult mice. Hematopoietic and intestinal progenitors were significantly depleted in Elavl1 conditionally deleted mice due to a p53-dependent cell death program. During embryonic development, Elavl1 embryos appeared normal at day 8.5; however, embryos could not survive beyond embryonic day 14.5 (E14.5). At E10.5 to E12.5,